Vitamin D analogues

ABSTRACT

The invention relates to novel bicyclic compounds having the general formula (I):                    
     as well as to a method for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, in carcinology and in the field of autoimmune diseases and that of organ or tissue transplants in particular), or alternatively in cosmetic compositions.

The invention relates, as novel and useful industrial products, tobiaromatic compounds which are vitamin D analogues. The invention alsorelates to a process for preparing them and to their use inpharmaceutical compositions intended for use in human or veterinarymedicine, or alternatively in cosmetic compositions.

The compounds according to the invention have pronounced activity in thefields of cell proliferation and differentiation and find applicationsmore particularly in the topical and systemic treatment ofdermatological (or other) complaints associated with a keratinizationdisorder, complaints with an inflammatory and/or immunoallergiccomponent and hyperproliferation of tissues of ectodermal origin (skin,epithelium, etc.), whether benign or malignant. These compounds can alsobe used to combat ageing or the skin, whether light-induced orchronological, and to treat cicatrization disorders.

The compounds according to the invention can also be used in cosmeticcompositions for body and hair hygiene.

Vitamin D is an essential vitamin for preventing and treatingmineralization defects of cartilage (rickets) and of bone(osteomalacia), and even of certain forms of osteoporosis in elderlypeople. However, it is now accepted that its functions extend wellbeyond regulating bone metabolism and calcium homeostasis. Among thesefunctions, mention may be made of its action on cell proliferation anddifferentiation and the control of the immune defences. Their discoveryhas opened the way to novel therapeutic approaches in dermatology,carcinology and in the field of autoimmune diseases and that of organ ortissue transplants.

An efficient therapeutic supply has long been confounded by the toxicityof this vitamin (occasionally fatal hypercalcaemia). Structuralanalogues of vitamin D are currently synthesized, some of which conserveonly the differentiating properties and have no action on calciummetabolism.

One of the aims of the present invention is to propose novel compoundswhich are structural analogues of vitamin D and which show selectiveactivity on cell proliferation and differentiation without displayingany hypercalcaemiant nature.

Another aim of the present invention is to propose novel compounds whichare analogues of vitamin D and which are more readily synthesized andthus more economical than those known previously.

Thus, the present invention relates to compounds which can berepresented by the general formula (I) below:

in which:

R₁ represents a hydrogen atom, a CH₃ radical or a radical—(CH₂)_(s)—OR₄,

R₂ represents a radical —(CH₂)_(t)—OR₅, s, t, R₄ and R₅ having themeanings given below,

X—Y represents a bonding group chosen from the bonding groups offormulae (a) to (i) below:

R₆ and W having the meanings given below,

Z represents a ring chosen from the rings of formulae (j) to (n) below:

R₇ and R8 having the meanings given below, it being understood that whenZ represents the rings of formula (k), (l) or (m), then X—Y cannotrepresent a bonding group of formula (c) or (d),

it being understood that when Z represents a ring of formula (n), thenX—Y preferably represents a bonding group of formula (c) or (d),

R₃ represents an alkyl chain containing from 4 to 8 carbon atomssubstituted with one or more hydroxyl groups, it being possible for thehydroxyl groups to be protected in the form of acetoxy, methoxy orethoxy, trimethylsilyloxy, tert-butyldimethylsilyloxy,tetrahydropyranyloxy and optionally also:

substituted with one or more lower alkyl or cycloalkyl groups and/or

substituted with one or more halogen atoms and/or

substituted with one or more CF₃ groups and/or

in which one or more carbon atoms of the chain are replaced with oxygen,sulphur or nitrogen atoms, it being possible for the nitrogen atoms tobe optionally substituted with lower alkyl radicals and/or

in which one or more single bonds of the chain are replaced with one ormore double and/or triple bonds,

R₃ being positioned on the ring para or meta to the bonding group X—Y,

s and t, which may be identical or different, being 1 or 2,

R₄ and R₅, which may be identical or different, represent a hydrogenatom, an acetyl radical, a benzoyl radical, a trimethylsilyl radical, atert-butyldimethylsilyl radical or a tetrahydropyranyl radical,

R₆ represents a hydrogen atom or a lower alkyl radical,

W represents an oxygen or sulphur atom or an —NH— radical which canoptionally be substituted with a lower alkyl radical,

R₇ represents a hydrogen atom or a lower alkyl radical,

R₈ represents a hydrogen atom, a lower alkyl radical or a halogen atom.

The invention is also directed towards the optical and geometricalisomers of the said compounds of formula (I), as well as towards thesalts thereof when X—Y represent a bonding group of formulae (c) and (h)and W represents an —NH— radical optionally substituted with a loweralkyl radical.

When the compounds according to the invention are in the form of salts,they are pharmaceutically or cosmetically acceptable salts obtained byaddition of an inorganic or organic acid, in particular hydrochloricacid, sulphuric acid, acetic acid, fumaric acid, hemisuccinic acid,maleic acid or mandelic acid.

According to the present invention, the expression “lower alkyl radical”means a linear or branched radical containing from 1 to 6 carbon atoms,and preferably methyl, ethyl, isopropyl, tert-butyl and hexyl radicals.

The expression “cycloalkyl radical” means a cyclic or polycyclic alkaneradical containing from 3 to 10 carbon atoms. The cycloalkyl radical ispreferably chosen from a cyclopropyl, cyclopentyl or cyclohexyl radical.

The expression “halogen atom” preferably means a fluorine, chlorine orbromine atom.

Among the compounds of formula (I) falling within the context of thepresent invention, mention may be made in particular of the following:

(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

(E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

(E)-7-[2-(3,4-bis-hydroxymethyl-phenoxymethyl)-4-thienyl]-3-ethyloct-6-en-3-ol

(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-pyridyl]-3-ethyloct-6-en-3-ol

(E)-7-[6-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-pyridyl)-3-ethylnon-6-en-3-ol

(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol

(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1,2,2-pentafluoro-3-pentafluoroethylnona-4,6-dien-3-ol

(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethyl-4,4-dimethylnon-6-en-3-ol

(E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

(4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

((4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1,2,2-pentafluoro-3-pentafluoro-ethylnona-4,6-dien-3-ol

(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-benzylamino)-2-thienyl]-3-ethylnona-4,6-dien-3-ol

(4E,6E)-7-{5-[(3,4-bis-hydroxymethyl-benzyl)methyl-amino]-2-thienyl}-3-ethylnona-4,6-dien-3-ol

(4E,6E)-7-{5-[(3,4-bis-hydroxymethyl-benzyl)propyl-amino]-2-thienyl}-3-ethylnona-4,6-dien-3-ol

(E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol

(4E,6E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

(E)-7-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

(4E,6E)-7-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnon-6-en-3-ol

(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

(E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-3-ethylnon-6-en-3-ol

(4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-3-ethylnona-4,6-dien-3-ol

(3E,5E)-6-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol.

According to the present invention, the compounds of formula (I) thatare more particularly preferred are those for which at least one, andpreferably all, of the following conditions are satisfied:

R₁ represents a —CH₃ or —(CH₂)_(s)OH radical,

R₂ represents a radical —(CH₂)_(t)OH,

X—Y represents a bonding group of formula (b), (c), (h) or (g),

R₃ is chosen from

an alkyl or alkenyl chain of 4 to 8 carbon atoms substituted with atleast one hydroxyl radical and at least one lower alkyl radical,

or an alkyl or alkenyl chain of 4 to 8 carbon atoms substituted with atleast one hydroxyl radical, at least one lower alkyl radical and atleast one CF₃ radical.

A subject of the present invention is also processes for preparing thecompounds of formula (I).

FIGS. 1 to 6 represent reaction schemes which can be carried out toprepare the compounds according to the invention.

Thus, the compounds of formula I(a) can be obtained (FIG. 1) by reactinga halo compound, preferably a bromo compound, (1) with a phenolic(Y=OH), thiophenolic (Y=SH) or aniline (Y=NH—COO-tert-butyl) derivative(3) in the presence of a base such as K₂CO₃ in a solvent such as acetoneor methyl ethyl ketone.

The compounds of formula I(a) can also be obtained (FIG. 1) by reactinga halo compound, preferably a bromo compound, (1) with the sodium orpotassium salt of a phenolic (Y=OH), thiophenolic (Y=SH) or aniline(Y=NH—COO-tert-butyl) derivative (3) in a solvent such asdimethylformamide (DMF).

The compounds of formula I(b) can be obtained (FIG. 1) by reacting abenzoic derivative (2) with a phenolic (Y=OH), thiophenolic (Y=SH) oraniline (Y=NH₂) derivative (3) in the presence of carbonyldiimidazole ordicyclohexylcarbodiimide in a solvent such as dichloromethane ortetrahydrofuran (THF).

The compounds of formula I(b) can also be obtained (FIG. 1) by reactinga benzoyl chloride (obtained by reacting a benzoic derivative (2) withthionyl chloride or oxalyl chloride) with a phenolic (Y=OH),thiophenolic (Y=SH) or aniline (Y=NH₂) derivative (3) in the presence ofa base such as triethylamine in a solvent such as dichloromethane ortetrahydrofuran (THF).

The compounds (1) and (2) can be obtained according to the reactionschemes given in FIGS. 2 and 3. These methods for preparing thecompounds (1) and (2) have the advantage of limiting the number ofpreparation steps.

In FIG. 2, (a) represents a reaction with BF₃ in dioxane, (b) representsa reaction with CH₃OCH₂Cl in the presence of sodium hydride in adimethylformamide solvent, (c) represents a reaction with n-butyllithiumin the presence of CO₂ in a solvent such as tetrahydrofuran, (d)represents a reaction with n-butyllithium in tetrahydrofuran followed bya reaction with dimethylformamide, (e) represents a reduction reactionwith sodium borohydride in a methanol-tetrahydrofuran solvent and (f)represents a reaction with carbon tetrabromide in the presence oftriphenylphosphine in a dichloromethane solvent.

In FIG. 3, (a) represents a reaction with BH₃ in dioxane, (b) representsa reaction with methanol in the presence of sulphuric acid, (c)represents a reaction with t-C₄H₉(CH₃)₂SiCl in the presence of imidazolein a dimethylformamide solvent, (d) represents a reaction with LiAlH₄ inether, (e) represents a reaction with benzoyl chloride in the presenceof triethylamine in a solvent such as tetrahydrofuran, (f) represents areaction with (C₄H₉)₄NF in a solvent such as tetrahydrofuran and (g)represents a reaction with carbon tetrabromide in the presence oftriphenylphosphine in a dichloromethane solvent.

The compounds of formula I(c) can be obtained (FIG. 4) by aHorner-Emmons reaction between the phosphonate derivative (7) (obtainedfrom the corresponding benzyl bromide by an Arbuzov reaction) and thealdehyde derivative (6). The derivative (6) can be obtained from thebromo ketone derivative (4), first by protecting the ketone function inthe form of dioxolane (5) and then by forming the lithium derivative andreaction with dimethylformamide.

The compounds of formula I(d) can be obtained from the compounds (8) byhydrogenation of the double bond in the presence ofpalladium-on-charcoal.

The compounds of formula I(c) can also be obtained (FIG. 5) by a Heckreaction between an ethylenic derivative (13) (obtained by reaction ofthe benzaldehyde (12) with methyltriphenylphosphonium bromide) and thetriflate (X=OSO₂CF₃) or iodo (X=I) derivative (15) in the presence of atransition metal catalyst such as Pd(Cl)₂(PPh₃)₂ in a solvent such astriethylamine.

The compounds of formula I(e) can be obtained (FIG. 5) by a Sonogashirareaction between an acetylenic derivative (14) (obtained from thebenzaldehyde (12) by a Corey-Fuchs reaction) and a triflate derivative(X=OSO₂CF₃) or iodo derivative (X=I) (15) in the presence of atransition metal catalyst such as Pd(Cl)₂(PPh₃)₂ and CuI in a solventsuch as triethylamine.

The chain R₃ can be introduced using, for example, the methods describedin Medicinal Research Reviews, Vol. 7, No. 2, 147-171 (1987) T. KAMETANIand H. FURUYAMA, Chem. Rev. Vol. 78, No. 3, 199-241 (1978) D. M. PIATAKand J. WICHA, or in Chem. Rev. Vol. 95, No. 6, 1877-1952 (1995) G. ZHUand W. H. OKAMURA.

Thus, as examples, a few summarized methods are given in FIG. 6 in which(a) represents a reaction withMgBr—CH₂—(CH₂)_(n)—C(CH₃)₂—O-tetrahydropyran in a solvent such astetrahydrofuran, (b) represents a reaction in the presence ofpara-toluenesulphonic acid or sulphuric acid, (c) represents ahydrogenation reaction in the presence of a catalyst such aspalladium-on-charcoal, (d) represents a reduction reaction with sodiumborohydride in a methanol-tetrahydrofuran solvent, (e) represents areaction with Br—CH₂—(CH₂)_(n)—CH₂—COOR in the presence of potassiumhydride in a dimethylformamide solvent, (f) represents a reaction withMgXAlkyl, X representing a halogen atom, in a solvent such astetrahydrofuran, (g) represents a reaction with NC—CH₂—P(O) (OC₂H₅)₂ inthe presence of sodium hydride in a solvent such as tetrahydrofuran, (h)represents a reaction with diisobutylaluminium hydride in a solvent suchas tetrahydrofuran, (i) represents a reaction with carbon tetrabromidein the presence of triphenylphosphine in a solvent such astetrahydrofuran followed by a reaction with n-butyllithium, (j)represents a reaction with n-butyllithium in a solvent such astetrahydrofuran, (k) represents a reaction with the alkyl chloroformateCl—COOR, (l) represents a reaction with MgXAlkyl, X representing ahalogen atom, in a solvent such as tetrahydrofuran, (m) represents areaction with n-butyllithium in a solvent such as tetrahydrofuran, (n)represents a reaction with CF₃—CO—CF₃, (0) represents a reaction withHOOC—(CH₂)₃—P(C₆H₅)₃Br in the presence of potassium tert-butoxide in asolvent such as tetrahydrofuran, (p) represents a reaction with ethanolin the presence of sulphuric acid, (q) represents a reaction withMgXAlkyl, X representing a halogen atom, in a solvent such astetrahydrofuran, (r) represents a reaction with ROOC—CH═CH—CH₂—P(O)(OC₂H₅)₂ in the presence of lithium diisopropylamide in a solvent suchas tetrahydrofuran, and (s) represents a reaction with an alkyllithiumderivative in a solvent such as tetrahydrofuran.

The compounds of general formula (I) have biological propertiesanalogous to those of vitamin D, in particular the properties oftransactivation of the vitamin D response elements (VDRE), such as anagonist or antagonist activity with respect to receptors of vitamin D orderivatives thereof. The expression “D vitamins or derivatives thereof”means, for example, the derivatives of vitamin D₂ or D3 and inparticular 1,25-dihydroxyvitamin D₃ (calcitriol).

This agonist activity with respect to receptors of vitamin D orderivatives thereof can be demonstrated “in vitro” by methods known inthe field of study of gene transcription (Hansen et al., The Society forInvestigative Dermatology, vol. 1, No. 1, April 1996).

By way of example, the VDR agonist activity can be tested on the HeLacell line by co-transfection with an expression vector for the human VDRreceptor and the reporter plasmid p240Hase-CAT which contains the region−1399 to +76 of rat 24-hydroxylase promoter, cloned upstream of theframe encoding the chloramphenicol-acetyl-transferase (CAT) gene. 18hours after co-transfection, the test product is added to the medium.After treatment for 18 hours, assay of the CAT activity in the celllysates is carried out by an ELISA test. The results are expressed aspercentages of the effect normally observed with 10⁻⁷M calcitriol.

The agonist activity can also be characterized in the co-transfectionsystem, by determining the dose required to reach 50% of the maximumactivity of the product (AC50).

The biological properties of the vitamin D analogues can also bemeasured by the capacity of the product to inhibit the proliferation ofnormal human keratinocytes (NHK in culture). The product is added toNHKs cultured under conditions which promote the proliferative state.The product is left in contact with the cells for 5 days. The number ofproliferative cells is measured by incorporation of bromodeoxyuridine(BRdU) into the DNA.

The vitamin D receptor agonist activity of the compounds of theinvention can also be evaluated “in vivo” by induction of 24-hydroxylasein SKH mice. (Voorhees et al., 1997.108: 513-518).

A subject of the present invention is also, as medicinal products, thecompounds of formula (I) as described above.

The compounds according to the invention are particularly suitable inthe following fields of treatment:

1) for treating dermatological complaints associated with akeratinization disorder which has a bearing on differentiation and onproliferation, in particular for treating simple acne, comedones,polymorphonuclear leukocytes, rosacea, nodulocystic acne, acneconglobata, senile acne and secondary acnes such as solar,medication-related or professional acne,

2) for treating other types of keratinization disorders, in particularichthyosis, ichthyosiform states, Darier's disease, palmoplantarkeratoderma, leukoplasias and leukoplasiform states, and cutaneous ormucous (buccal) lichen,

3) for treating other dermatological complaints with an inflammatoryand/or immunoallergic component, with or without cell proliferationdisorders, and, in particular, all forms of psoriasis, whether this iscutaneous, mucous or ungual psoriasis, and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy,

4) for treating all dermal or epidermal proliferations, whether benignor malignant and whether they are of viral origin or otherwise, such ascommon warts, flat warts and verruciform epidermodysplasia, oral orflorid papillomatoses, T lymphoma and proliferations which may beinduced by ultraviolet radiation, in particular in the case ofbasocellular and spinocellular epithelioma, as well as any pre-cancerousskin lesion such as keratoacanthomas,

5) for treating other dermatological disorders such as immune dermatitissuch as lupus erythematosus, immune bullosis and collagen diseases suchas scleroderma,

6) in the treatment of dermatological or general complaints with animmunological component,

7) for combating disorders of sebaceous function such thehyperseborrhoea of acne or simple seborrhoea,

8) in the treatment of skin disorders due to exposure to UV radiation,as well as for preparing or combating ageing of the skin, whether it islight-induced or chronological ageing, or for reducing actinic keratosesand pigmentations, or any pathologies associated with chronological oractinic ageing,

9) for preventing or treating cicatrization disorders or for preventingor repairing stretchmarks,

10) in the treatment of inflammatory complaints such as arthritis,

11) in the treatment of any complaint of viral origin on the skin orgenerally, such as Kaposi's syndrome,

12) for treating certain ophthalmological disorders, in particularcorneopathies,

13) in the treatment of prevention of cancerous or pre-cancerous statesof cancers presenting or possibly being induced by vitamin D receptors,such as, but without limitation, breast cancer, leukaemia,myelodysplasic syndromes and lymphomas, carcinomas of the Malpighianepithelial cells and gastrointestinal cancers, melanomas andosteosarcoma,

14) in the prevention or treatment of alopecia of various origins, inparticular alopecia due to chemotherapy or radiation,

15) in the treatment of immune system complaints, such as autoimmunediseases, for instance type 1 diabetes mellitus, multiple sclerosis,lupus and lupus-type complaints, asthma, glomerulonephritis, selectivedysfunctions of the immune system such as AIDS, or prevention of immunerejection such as kidney, heart, bone marrow, liver, pancreatic islet,pancreas or skin graft rejection, or prevention of graft-versus-hostdisease,

16) in the treatment of endocrine complaints, given that the vitamin Danalogues can modify hormonal secretion such as increasing the secretionof insulin or selectively suppressing the secretion of parathyroidhormone, for example in chronic renal insufficiency and secondaryhyperparathyroidism,

17) in the treatment of complaints characterized by abnormal managementof intracellular calcium, and in the treatment or prevention ofpathologies in which calcium metabolism is involved, such as muscularischaemia (myocardial infarction),

18) in the treatment or prevention of vitamin D deficiencies and othermineral homeostasis complaints in plasma and bone, such as rickets,osteomalacia, osteoporosis, in particular in the case of menopausalwomen, renal osteodystrophy and parathyroid function disorders,

19) in the treatment of complaints of the cardiovascular system such asarteriosclerosis or hypertension, as well as non-insulin-dependentdiabetes.

In the therapeutic fields mentioned above, the compounds according tothe invention can advantageously be used in combination with retinoids,with corticosteroids or oestrogens, in combination with antioxidants,with α-hydroxy or α-keto acids or derivatives thereof, withpotassium-channel blockers, or alternatively in combination with othermedicinal products known to interfere with the immune system (forexample cyclosporin, FK 506, glucocorticoids, monoclonal antibodies,cytokines or growth factors, etc.).

The term “retinoids” means either natural or synthetic RAR- orRXR-receptor ligands.

The expression “free-radical scavengers” means, for example,α-tocopherol, superoxide dismutase, ubiquinol or certain metal-chelatingagents.

The expression “α-hydroxy or α-keto acids or derivatives thereof” means,for example, lactic acid, malic acid, citric acid, glycolic acid,mandelic acid, tartaric acid, glyceric acid, ascorbic acid and salicylicacid derivatives, as well as salts, amides or esters thereof.

The expression “potassium-channel blockers” means, for example,Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivativesthereof.

A subject of the present invention is also a pharmaceutical compositioncomprising at least one compound of formula (I) as defined above.

A subject of the present invention is thus also such a pharmaceuticalcomposition intended in particular for treating the abovementionedcomplaints.

The compounds according to the invention can be administered via theenteral, parenteral, topical or ocular route.

Via the enteral route, the pharmaceutical compositions can be in theform of tablets, gel capsules, sugar-coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, microspheres ornanospheres or lipid vesicles or polymer vesicles allowing controlledrelease. Via the parenteral route, the compositions can be in the formof solutions or suspensions for infusion or for injection. The compoundsaccording to the invention are generally administered at a daily dose ofabout from 0.001 μg/kg to 1000 μg/kg and preferably of about from 0.01μg/kg to 100 μg/kg of bodyweight in 1 to 3 dosage intakes.

Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are intended for treating the skinand mucous membranes and are in the form of ointments, creams, milks,salves, powders, impregnated pads, solutions, gels, sprays, lotions orsuspensions. They can also be in the form of microspheres or nanospheresor lipid vesicles or polymer vesicles or polymer patches and hydrogelsallowing controlled release. These topical-route compositions can beeither in anhydrous form or in aqueous form depending on the clinicalindication.

Via the ocular route, they are mainly eye drops.

These topical-route or ocular-route compositions contain at least onecompound of formula (I) as defined above at a concentration preferablyof between 0.0001% and 5% and preferably between 0.001% and 1% relativeto the total weight of the composition.

The compounds of formula (I) according to the invention also find anapplication in the cosmetics field, in particular in body and hairhygiene and especially for treating skin with a tendency towards acne,for regrowth of the hair, for preventing hair loss, for combating thegreasy appearance of the skin or the hair, in protecting against theharmful effects of sunlight or in treating physiologically dry skin, forpreventing and/or combating light-induced or chronological ageing.

In the cosmetics field, the compounds according to the invention canadvantageously be used in combination with retinoids, withcorticosteroids, in combination with free-radical scavengers, withα-hydroxy or α-keto acids or derivatives thereof, or alternatively withion-channel blockers, the various products taken in combination with thecompounds of the present invention being as defined above.

The present invention is thus also directed towards a cosmeticcomposition containing, in a cosmetically acceptable support, at leastone compound of formula I as defined above. This cosmetic compositioncan be in particular in the form of a cream, a milk, a lotion, a gel,microspheres or nanospheres or lipid vesicles or polymer vesicles, asoap or a shampoo.

The concentration of compound of formula I in the cosmetic compositionscan be between 0.001% and 3% by weight relative to the total weight ofthe composition.

The pharmaceutical and cosmetic compositions according to the inventioncan also contain inert or even pharmacodynamically or cosmeticallyactive additives or combinations of these additives and, in particular:wetting agents; depigmenting agents such as hydroquinone, azaleic acid,caffeic acid or kojic acids; emollients; moisturizing agents such asglycerol, PEG 400, thiamorpholinone and derivatives thereof or urea;antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine orS-benzylcysteamine and salts and derivatives thereof, or benzoylperoxide; antibiotics such as erythromycin and esters thereof, neomycin,clindamycin and esters thereof, tetracyclines; antifungal agents such asketoconazole or poly-4,5-methylene-3-isothiazolinones; agents forpromoting regrowth of the hair, such as Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof,Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andPhenytoin (5,4-diphenylimidazolidine-2,4-dione); non-steroidalanti-inflammatory agents; carotenoids, and in particular β-carotene;anti-psoriatic agents such as anthralin and derivatives thereof, and,finally, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoicacid, and esters and amides thereof.

The compositions according to the invention can also contain flavourenhancers, preserving agents such as para-hydroxybenzoic acid esters,stabilizers, moisture regulators, pH regulators, osmotic pressuremodifiers, emulsifiers, UV-A and UV-B screening agents, antioxidantssuch as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene.

Several examples of the production of active compounds of formula (I)according to the invention, and several concrete formulations based onsuch compounds, and an example of a test for evaluating the biologicalactivity of compounds of formula (I) according to the invention, willnow be given by way of illustration and with no limiting nature.

EXAMPLE 1(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

a) 4-Aminophthalic Acid

1 g (4.73 mmol) of 4-nitrophthalic acid is dissolved in 10 mL ofanhydrous ethanol. The solution is stirred at room temperature anddegassed under argon. 50 mg of palladium/charcoal (5%) are added in asingle portion and hydrogen is bubbled into the solution. After 3 hours,the solution is filtered through Celite and then evaporated.

Orange-coloured oil. m=820 mg. Y=96%. ¹H NMR (DMSO): 3.32 (1H, s), 5.95(1H, s), 6.49-6.53 (2H, m), 7.46-7.50 (1H, d, J=8.8 Hz), 12.33 (2H,COOH, s).

b) Methyl 4-Hydroxyphthalate

A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 mL ofsulphuric acid (1 M) is cooled to 0° C. A solution of 2.27 g of sodiumnitrite in 6 mL of water is then added slowly. After 15 minutes at 0°C., 15 mL of concentrated sulphuric acid are added and the mixture ismaintained at 100° C. with vigorous stirring for 1 hour. At roomtemperature, the reaction medium is extracted with ethyl acetate andwashed with water. After separation of the phases by settling, theorganic phase is dried over magnesium sulphate and concentrated. Theresidue is purified on a column of silica (80 dichloromethane/20methanol). It is then dissolved in 100 mL of methanol and refluxed with2 mL of sulphuric acid. After disappearance of the diacid, the methanolis evaporated off and the product is taken up in ethyl acetate andwashed with water. The organic phase is separated out after settling,dried over sodium sulphate and evaporated.

M=5.2 g. Y=90%. ¹H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86(2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).

c) Ethyl (E)-5-(Bromo-2-thienyl)-4-hexenoate

22.2 g (51.7 mmol) of (3-carboxypropyl)triphenylphosphonium bromide aredried under vacuum for 1 h with heating at 130° C., and then cooled toroom temperature and dissolved in 200 mL of anhydrous THF. 11.5 g (102.5mmol) of potassium tert-butoxide in 100 mL of THF are then added slowly,after which the orange-red mixture is stirred for 15 minutes. A solutionof 7 g (34 mmol) of 1-(5-bromo-2-thienyl)ethanone in 100 mL of THF isthen added dropwise and the reaction medium is stirred for 15 hours.After treatment with saturated ammonium chloride solution, extractionwith ethyl acetate, drying and evaporation of the solvents from theorganic phase, the residue obtained is purified by chromatography on acolumn of silica. An ochre-coloured solid is obtained (m.p.: 62-64° C.,m=5.8 g; Y=62%). This product is then dissolved in 100 mL of ethanol and2 mL of sulphuric acid are then added. The reaction medium is brought toreflux and stirred for 2 hours. After treatment with water, the mediumis extracted with ethyl acetate and the organic phases are thencombined, dried and concentrated under reduced pressure. The residueobtained is purified by chromatography on a column of silica (eluent: 95heptane/5 ethyl acetate) to give the pure trans isomer in the form of ayellow oil (m=3.4 g; Y=77%).

d) (E)-7-(5-Bromo-2-thienyl)-3-ethyloct-6-en-3-ol

3.3 g of ethyl (E)-5-(5-bromo-2-thienyl)-4-hexenoate (10.9 mmol) aredissolved in 50 mL of ethyl ether. 22 mL of 2.0 M ethylmagnesiumchloride solution (44 mmol) are then added dropwise and the reactionmedium is stirred at room temperature for 30 minutes. After treatmentwith saturated ammonium chloride solution, extraction with ethyl etherand then drying and evaporation of the solvents from the organic phase,the residue obtained is purified by chromatography on a column ofsilica. A colourless oil is obtained (m=2.4 g; Y=70%).

e) [(E)-5-(5-Bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane

2.2 g (6.9 mmol) of (E)-7-(5-bromo-2-thienyl)-3-ethyloct-6-en-3-ol aredissolved in 50 mL of dichloromethane. 25 mg (0.2 mmol) of4-dimethylaminopyridine and 4.8 mL of triethylamine (34.8 mmol) areadded and the reaction medium is cooled to 0° C. 3.9 mL (17.4 mmol) oftriethylsilyl trifluoromethanesulphonate are added dropwise. After theaddition, the reaction medium is warmed to room temperature and thentreated with water and extracted with dichloromethane. After separationof the phases by settling, drying and concentration of the organicphases under reduced pressure, the residue obtained is purified bychromatography on a column of silica. A yellow oil is obtained (m=2.3 g;Y=97%).

f)[5-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]methanol

2.8 g (6.5 mmol) of[(E)-5-(5-bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane aredissolved in 50 mL of anhydrous THF and the mixture is then cooled to−78° C. 2.9 mL (7.1 mmol) of 2.5 M butyllithium solution are then added,after which the reaction medium is stirred for 15 minutes. 0.55 mL ofanhydrous DMF is then added, after which the reaction medium is warmedto room temperature and stirred for 1 h. After treatment with saturatedammonium chloride solution and then extraction with ethyl acetate, theorganic phases are combined, dried and concentrated under reducedpressure. The residue containing the desired5-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)thiophene-2-carbaldehydeis then dissolved in 50 mL of anhydrous methanol, after which 150 mg(3.9 mmol) of sodium borohydride are added in two portions. Afterstirring for 10 minutes, the medium is treated with ammonium chloridesolution and extracted with ethyl ether. The organic phases arecombined, dried and concentrated under reduced pressure. Afterpurification by chromatography on a column of silica, a yellow oil isobtained (m=1.76 g; Y=71%).

g) Dimethyl4-[5-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalate

1 g (2.6 mmol) of[5-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]methanolis dissolved in 50 mL of dichloromethane and cooled to 0° C. 0.55 mL(3.9 mmol) of triethylamine is added, followed by 220 mL ofmethylsulphonyl chloride (2.9 mmol). After stirring for 20 minutes, thereaction medium is treated with ammonium chloride solution and extractedwith dichloromethane. The organic phases are combined, dried andconcentrated under reduced pressure. The residue obtained is thenpurified by chromatography on a column of silica to yield the desiredproduct.

h) Dimethyl4-[5-((E)-5-Ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalate

750 mg (1.3 mmol) of dimethyl4-[5-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalateare dissolved in 30 mL of THF. 2.6 mL (2.6 mmol) of a 1.0 Mtetrabutylammonium fluoride solution are added and the reaction mediumis heated at 60° C. for 3 hours. After treatment with ammonium chloridesolution and extraction with ethyl acetate, the organic phases arecombined, dried and concentrated under reduced pressure. The residue ispurified by chromatography on a column of silica. A yellow oil isobtained (m=355 mg; Y=59%).

i)(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

350 mg (0.76 mmol) of dimethyl4-[5-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalateare dissolved in 20 mL of anhydrous ethyl ether. 70 mg (1.8 mmol) oflithium aluminium hydride are added and the reaction medium is stirredat room temperature for 30 minutes. 400 mL of water are then addedslowly and the medium is filtered. The filtrate is concentrated underreduced pressure and the residue obtained is then purified bychromatography on a column of silica (eluent: 70 ethyl acetate/30heptane). A white solid (m.p.: 100-102° C.) is obtained (m=175 mg;Y=58%).

¹H NMR (DMSO): 0.82 (t, 6H, J=7.3 Hz), 1.42 (q, 4H, J=7.4 Hz), 2.03 (s,3H), 2.1-2.25 (m, 2H), 3.97 (s, 1H), 4.49 (d, 2H, J=5.3 Hz), 4.58 (d,2H, J=5. 3 Hz), 5.00 (t, 1H), 5.17 (t, 1H), 5.26 (s, 2H), 5.92 (t, 1H),6.90-6.97 (m, 2H), 7.10 (m, 2H), 7.3 (m, 2H).

EXAMPLE 2(E)-7-[4-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

a) Ethyl (E)-5-(4-Bromo-2-thienyl)-4-hexenoate

In a manner similar to that of Example 1(c), by reaction of 18.8 g (43.9mmol) of (3-carboxypropyl)triphenylphosphonium bromide with 6 g (29.2mmol) of 1-(4-bromo-2-thienyl)ethanone, 6 g (75%) of(E)-5-(4-bromo-2-thienyl)-4-hexenoic acid are obtained, which product isconverted into 5.8 g (88%) of ethyl(E)-5-(4-bromo-2-thienyl)-4-hexenoate.

b) (E)-7-(4-Bromo-2-thienyl)-3-ethyloct-6-en-3-ol

In a manner similar to that of Example 1(d), starting with 6.3 g ofethyl (E)-5-(4-bromo-2-thienyl)-4-hexenoate (10.9 mmol), 6.6 g (100%) ofthe expected alcohol are obtained in the form of an orange-coloured oil.

c) [(E)-5-(4-Bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane

In a manner similar to that of Example 1(e), starting with 6.6 g (20.3mmol) of the above alcohol, 6.6 g (73%) of[(E)-5-(4-bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane areobtained in the form of a colourless oil.

d)[2-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-4-thienyl]methanol

In a manner similar to that of Example 1(f), starting with 6.2 g (14.3mmol) of[(E)-5-(4-bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane, 1.7g (29%) of[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]carbaldehydeare obtained, which product is reduced in the presence of NaBH₄ to give1.58 g (92%) of[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]methanol.

e) Dimethyl4-[2-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-4-thienylmethoxy]phthalate

In a manner similar to that of Example 1(g), starting with 500 mg of theabove alcohol, 220 mg (30%) of dimethyl4-[2-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-4-thienylmethoxy]phthalateare obtained in the form of a yellow oil.

f) Dimethyl4-[2-((E)-5-Ethyl-5-hydroxy-1-methylhept-1-enyl)-4-thienylmethoxy]phthalate

In a manner similar to that of Example 1(h), starting with 210 mg (0.36mmol) of dimethyl4-[2-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-4-thienylmethoxy]phthalate,90 mg (53%) of dimethyl4-[2-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-4-thienylmethoxy]phthalateare obtained.

g)(E)-7-[4-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol

In a manner similar to that of Example 1(i), by treatment of dimethyl4-[4-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalate(61 mg; 0.13 mmol) with 20 mg of lithium aluminium hydride, a whitesolid (m.p.: 95-97° C.) is obtained after purification by chromatographyon a column of silica (m=39 mg; Y=73%).

¹H NMR (DMSO): 0.77 (t, 6H, J=7.3 Hz), 1.36 (q, 4H, J=7.3 Hz), 1.94 (s,3H), 2.0-2.15 (m, 2H), 3.89 (s, 1H), 4.41 (d, 2H, J=5.3 Hz), 4.50 (d,2H, J=5.3 Hz), 4.92 (t, 1H), 5.08 (t, 1H), 5.17 (s, 2H), 5.85 (t, 1H),6.80-6.88 (m, 2H), 7.02 (m, 2H), 7.2 (m, 2H).

EXAMPLE 3(E)-7-[2-(3,4-bis-Hydroxymethyl-phenoxymethyl)-4-thienyl]-3-ethyloct-6-en-3-ol

a) Ethyl (E)-5-(2-Bromo-4-thienyl)-4-hexenoate

In a manner similar to that of Example 1(c), by reaction of 19.1 g (44.6mmol) of (3-carboxypropyl)triphenylphosphonium bromide with 6.1 g (29.7mmol) of 1-(2-bromo-4-thienyl)ethanone, 5.9 g (72%) of(E)-5-(2-bromo-4-thienyl)-4-hexenoic acid are obtained, which product isconverted into 4.1 g (63%) of ethyl(E)-5-(2-bromo-4-thienyl)-4-hexenoate.

b) (E)-7-(2-Bromo-4-thienyl)-3-ethyloct-6-en-3-ol

In a manner similar to that of Example 1(d), starting with 4.1 g ofethyl (E)-5-(2-bromo-4-thienyl)-4-hexenoate (13.5 mmol), 3.2 g (75%) ofthe expected alcohol are obtained in the form of an orange-coloured oil.

c) [(E)-5-(2-Bromo-4-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane

In a manner similar to that of Example 1(e), starting with 3.2 g (11mmol) of the above alcohol, 4.2 g (96%) of[(E)-5-(2-bromo-4-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane areobtained in the form of a colourless oil.

d)[4-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]methanol

In a manner similar to that of Example 1(f), starting with 4.1 g (9.5mmol) of[(E)-5-(2-bromo-4-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane, 2 g(55%) of[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]carbaldehyde,which product is reduced in the presence of NaBH₄ to give 2 g (99%) of[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienyl]methanol.

e) Dimethyl4-[4-((E)-5-Ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalate

In a manner similar to that of Example 1(g), starting with 1 g (2.6mmol) of the above alcohol, 400 mg (27%) of dimethyl4-[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalateare obtained in the form of a yellow oil.

f) Dimethyl4-[4-((E)-5-Ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalate

In a manner similar to that of Example 1(h), starting with 350 mg (0.6mmol) of dimethyl4-[4-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalate,190 mg (68%) of dimethyl4-[4-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalateare obtained.

g)(E)-7-[2-(3,4-bis-Hydroxymethyl-phenoxymethyl)-4-thienyl]-3-ethyloct-6-en-3-ol

In a manner similar to that of Example 1(i), by treatment of dimethyl4-[5-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-3-thienylmethoxy]phthalate(180 mg; 0.39 mmol) with 36 mg of lithium aluminium hydride (0.9 mmol),a colourless oil is obtained after purification by chromatography on acolumn of silica (m=115 mg; Y=73%).

¹H NMR (DMSO): 0.85 (t, 6H, J=7.3 Hz), 1.43 (q, 4H, J=7.4 Hz), 1.98 (s,3H), 2.13-2.20 (m, 2H), 3.95 (s, 1H), 4.49 (d, 2H, J=5.3 Hz), 4.58 (d,2H, J=5.3 Hz), 5.00 (t, 1H, J=5.4 Hz), 5.16 (t, 1H, J=5.5 Hz), 5.27 (s,2H), 5.98 (t, 1H), 6.92 (dd, 1H, J₁=2.6 Hz, J₂=8.3 Hz), 7.10 (d, 1H,J=2.5 Hz), 7.28-7.35 (m, 2H), 7.44 (s, 1H).

EXAMPLE 4(E)-7-[6-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-pyridyl]-3-ethylnon-6-en-3-ol

a) Ethyl (E)-5-(6-Bromo-2-pyridyl)-4-heptenoate

In a manner similar to that of Example 1(c), by reaction of 29.8 g (69.3mmol) of (3-carboxypropyl)triphenylphosphonium bromide with 9.9 g (46.2mmol) of 1-(6-bromo-2-pyridyl)propanone, 8.9 g (68%) of(E)-5-(6-bromo-2-pyridyl)-4-heptenoic acid are obtained, which productis converted into 7.8 g (80%) of ethyl(E)-5-(6-bromo-2-pyridyl)-4-heptenoate.

b) (E)-7-(6-Bromo-2-pyridyl)-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 1(d), starting with 7.4 g ofethyl (E)-5-(6-bromo-2-pyridyl)-4-heptenoate (23.7 mmol), 7.3 g (94%) ofthe expected alcohol are obtained in the form of an orange-coloured oil.

c) [(E)-5-(6-Bromo-2-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane

In a manner similar to that of Example 1(e), starting with 7.5 g (23mmol) of the above alcohol, 9.8 g (97%) of[(E)-5-(6-bromo-2-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane areobtained in the form of a colourless oil.

d)[6-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridyl]methanol

In a manner similar to that of Example 1(f), starting with 8.8 g (20mmol) of[(E)-5-(6-bromo-2-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane, 5.8g (75%) of[6-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridyl]carbaldehyde,which product is reduced in the presence of NaBH₄ to give 5.8 g (99%) of[6-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridyl]methanol.

e) Dimethyl4-[6-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridylmethoxy]phthalate

In a manner similar to that of Example 1(g), starting with 1 g (2.55mmol) of the above alcohol, 1.2 g (81%) of dimethyl4-[6-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridylmethoxy]phthalateare obtained in the form of a yellow oil.

f) Dimethyl4-[6-((E)-1,5-Diethyl-5-hydroxyhept-1-enyl)-2-pyridylmethoxy]phthalate

In a manner similar to that of Example 1(h), starting with 1.1 g (1.88mmol) of dimethyl4-[6-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-2-pyridylmethoxy]phthalate,740 mg (84%) of dimethyl4-(6-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-2-pyridylmethoxy]phthalateare obtained.

g)(E)-7-[6-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-pyridyl]-3-ethylnon-6-en-3-ol]-3-ethyloct-6-en-3-ol

In a manner similar to that of Example 1(i), by treatment of dimethyl4-[6-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-2-pyridylmethoxy]phthalate(740 mg; 1.57 mmol) with 145 mg of lithium aluminium hydride (3.8 mmol),a colourless oil is obtained after purification by chromatography on acolumn of silica (m=515 mg; Y=79%).

¹H NMR (CDCl₃): 0.88 (t, 6H, J=7.4 Hz), 1.04 (t, 3H, J=7.5 Hz),1.48-1.64 (m, 6H), 1.7 (bs, 1H), 2.24-2.33 (m, 2H), 2.65 (q, 2H, J=7.5Hz), 3.1 (bs, 1H), 3.3 (bs, 1H), 4.65 (s, 2H), 4.68 (s, 2H), 5.16 (s,2H), 6.24 (t, 1H, J=7.3 Hz), 6.88 (dd, 1H, J₁=2.6 Hz, J₂=8.3 Hz), 7.03(d, 1H, J=2.6 Hz), 7.20-7.32 (m, 3H), 7.62 (t, 1H, J=7.8 Hz).

EXAMPLE 5(E)-7-[5-(3,4-bis-Hydroxymethyl-phen(oxymethyl)-3-pyridyl]-3-ethylnon-6-en-3-ol

a) 5-Bromo-N-methoxy-N-methylnicotinamide

40 g (198 mmol) of 5-bromonicotinic acid are dissolved in 300 mL of THFand treated with 19 mL of oxalyl chloride at 0° C. 66 mL (475 mmol) oftriethylamine are then added, followed by 23.2 g (237 mmol) ofN,O-dimethylhydroxylamine hydrochloride. After stirring at roomtemperature for 4 hours, the reaction medium is poured into water andextracted with ethyl acetate. The organic phase is separated out aftersettling, dried over magnesium sulphate and evaporated. 45.1 g (93%) ofthe expected product are collected in the form of a light brown oil.

b) 1-(5-Bromo-3-pyridyl)propanone

44 g (180 mmol) of 5-bromo-N-methoxy-N-methylnicotinamide are dissolvedin 200 mL of THF and 60 mL (180 mmol) of ethylmagnesium chloridesolution (3M in ethyl ether) are added dropwise. The reaction medium isstirred at room temperature for one hour, poured into water andextracted with ethyl acetate. The organic phase is separated out aftersettling, dried over magnesium sulphate and evaporated. The residueobtained is purified by chromatography on a column of silica eluted witha mixture of heptane and ethyl acetate (70/30). 4 g (11%) of1-(5-bromo-3-pyridyl)propanone are collected.

c) Ethyl (E)-5-(5-Bromo-3-pyridyl)-4-heptenoate

In a manner similar to that of Example 1(c), by reaction of 12 g (28mmol) of (3-carboxypropyl)triphenylphosphonium bromide with 4 g (18.6mmol) of 1-(5-bromo-3-pyridyl)propanone, 4.45 g (84%) of(E)-5-(5-bromo-3-pyridyl)-4-heptenoic acid are obtained, which productis converted into 3.6 g (74%) of ethyl(E)-5-(5-bromo-3-pyridyl)-4-heptenoate.

d) (E)-7-(5-Bromo-3-pyridyl)-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 1(d), starting with 2.6 g ofethyl (E)-5-(5-bromo-3-pyridyl)-4-heptenoate (8.3 mmol), 2.3 g (85%) ofthe expected alcohol are obtained in the form of an orange-coloured oil.

e) [(E)-5-(5-Bromo-3-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane

In a manner similar to that of Example 1(e), starting with 2.3 g (7mmol) of the above alcohol, 2.9 g (93%) of[(E)-5-(5-bromo-3-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane areobtained in the form of a colourless oil.

f)[5-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridyl]methanol

In a manner similar to that of Example 1(f), starting with 2.9 g (6.6mmol) of[(E)-5-(5-bromo-3-pyridyl)-1,1-diethylhept-4-enyloxy]triethylsilane, 775mg (30%) of[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridyl]carbaldehydeare obtained, which product is reduced in the presence of NaBH₄ to give774 mg (99%) of[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridyl]methanol.

g) Dimethyl4-[5-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridylmethoxy]phthalate

In a manner similar to that of Example 1(g), starting with 750 mg (1.9mmol) of the above alcohol, 140 mg (13%) of dimethyl4-[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridylmethoxy]phthalateare obtained in the form of a yellow oil.

h) Dimethyl4-[5-((E)-1,5-Diethyl-5-hydroxyhept-1-enyl)-3-pyridylmethoxy]phthalate

In a manner similar to that of Example 1(h), starting with 100 mg (0.17mmol) of dimethyl4-[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-pyridylmethoxy]phthalate,66 mg (82%) of dimethyl4-[5-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-3-pyridylmethoxy]phthalateare obtained.

i)(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-pyridyl]-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 1(i), by treatment of 60 mg (0.13mmol) of dimethyl4-[5-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-3-pyridylmethoxy]phthalatewith 12 mg of lithium aluminium hydride, a colourless oil is obtainedafter purification by chromatography on a column of silica (m=25 mg;Y=47%).

¹H NMR (CDCl₃): 0.90 (t, 6H, J=7.4 Hz), 0.98 (t, 3H, J=7.4 Hz),1.48-1.60 (m, 6H), 2.20-2.26 (m, 2H), 2.52 (q, 2H, J=7.4 Hz), 4.69 (s,2H), 4.71 (s, 2H), 5.04 (s, 2H), 5.69 (t, 1H, J=7.3 Hz), 6.87 (dd, 1H,J₁=2.7 Hz, J₂=8.3 Hz), 7.02, (d, 1H, J=2.6 Hz), 7.25-7.28 (m, 1H), 7.72(m, 2H), 8.4 (bs, 1H), 8.5 (bs, 1H).

EXAMPLE 6(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol

a) 2-Ethyl-2-2-thienyl-[1,3]dioxolane

30 g (214.3 mmol) of 1-2-thienyl-1-propanone are dissolved in 120 mL ofethylene glycol. 93 g (856 mmol) of trimethylsilyl chloride are thenadded. The reaction medium is stirred at room temperature for 24 hours.After treatment with water, the medium is extracted with ethyl acetateand the organic phases are then combined, dried and concentrated underreduced pressure. The residue obtained is purified by chromatography ona column of silica (eluent: 90 heptane/10 ethyl acetate). A yellow oilis obtained (m=15 g; Y=38%).

b) 5-(2-Ethyl-[1,3]dioxolan-2-yl)thiophene-2-carbaldehyde

15 g (81.4 mmol) of 2-ethyl-2-2-thienyl-[1,3]dioxolane are dissolved in300 mL of anhydrous THF and the mixture is then cooled to −78° C. 53 mL(89 mmol) of 1.7 M tert-butyllithium solution are then added, afterwhich the reaction medium is stirred for 1 hour. 10 mL (120 mmol) ofanhydrous DMF are then added and the medium is stirred for 1 hour. Thereaction medium is treated at −78° C. with 1N hydrochloric acid solutionand is then extracted with ethyl acetate and the organic phases arecombined, dried and concentrated under reduced pressure. The residueobtained is purified by chromatography on a column of silica. A yellowoil is obtained (m=19 g; Y=100%).

c) [5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienyl]methanol

9.5 g (44.7 mmol) of5-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-2-carbaldehyde are dissolved in100 mL of anhydrous methanol and the mixture is then cooled to 0° C.

2.2 g (58.1 mmol) of sodium borohydride are then added portionwise.After stirring for 1 hour, the medium is treated with ammonium chloridesolution and extracted with ethyl acetate. The organic phases arecombined, dried and concentrated under reduced pressure. Afterpurification by chromatography on a column of silica, a yellow oil isobtained (m=9.25 g; Y=96%).

d) 5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienylmethyl Methanesulphonate

9.25 g (43.2 mmol) of [5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]methanolare dissolved in 500 mL of dichloromethane and cooled to 0° C. 9.0 mL(64.7 mmol) of triethylamine are added, followed by 3.5 mL ofmethylsulphonyl chloride (45.3 mmol). After stirring for 1 hour, thereaction medium is treated with ammonium chloride solution and extractedwith dichloromethane. The organic phases are combined, dried andconcentrated under reduced pressure. A brown oil is obtained (m=9.28 g;Y=75%).

e) Dimethyl 4-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]phthalate

9.25 g (43.2 mmol) of 5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethylmethanesulphonate are dissolved in 100 mL of 2-butanone, and 9.07 g(43.2 mmol) of dimethyl 4-hydroxyphthalate (prepared in Example 1(b)), 6g of potassium carbonate (43.2 mmol) and 20 mg of sodium iodide areadded. The mixture is refluxed for 12 hours, cooled and filtered. Thefiltrate is concentrated under reduced pressure and then purified bychromatography on a column of silica. A yellow oil is obtained (m=12.70g; Y=73%).

f){5-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]-2-hydroxymethylphenyl}methanol

12.7 g (31.5 mmol) of dimethyl4-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]phthalate aredissolved in 500 mL of anhydrous ethyl ether. 2.87 g (75.7 mmol) oflithium aluminium hydride are added and the reaction medium is stirredat 0° C. for 1 hour. 2.9 mL of water are then added slowly, followed by2.9 mL of aqueous 15% sodium hydroxide, and then 8.7 mL of water arealso added slowly. After stirring for 20 minutes, the medium is thenfiltered. The filtrate is concentrated under reduced pressure and theresidue obtained is then purified by chromatography on a column ofsilica. A white solid (m.p.: 78-80° C.) is obtained (m=8 g; Y=72%).

g) 1-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-1-propanone

8 g (22.8 mmol) of{5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]-2-hydroxymethylphenyl}methanolare dissolved in 75 mL of water and 75 mL of acetone. 1 g ofpara-toluenesulphonic acid is then added and the reaction medium isrefluxed for 1 hour. The reaction medium is treated with sodiumbicarbonate solution and extracted with ethyl acetate. The organicphases are combined, washed with water, dried and concentrated underreduced pressure. A white powder (m.p.=123° C.) is obtained (m=6.9 g;Y=100%).

h)1-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1-propanone

6.9 g (22.8 mmol) of1-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1-propanone aredissolved in 70 mL of anhydrous DMF. 4.3 g (63.8 mmol) of imidazole and7.5 g (50 mmol) of tert-butyldimethylchlorosilane are then addedportionwise. The reaction medium is stirred at room temperature for 12hours. The resulting mixture is treated with water and extracted withethyl acetate. The organic phases are combined, dried and concentratedunder reduced pressure and the residue obtained is then purified bychromatography on a column of silica. A colourless oil is obtained(m=11.5 g; Y=100%).

i)(E)-5-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoicAcid

6.7 g (15.6 mmol) of (3-carboxypropyl)triphenylphosphonium bromide aredried under vacuum for 1 h by heating at 130° C. and then cooled to roomtemperature and dissolved in 70 mL of anhydrous THF. 3.5 g (31.2 mmol)of potassium tert-butoxide are then added slowly and the orange-redmixture is then stirred for 15 minutes. A solution of 5.7 g (10.4 mmol)of1-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1-propanonein 70 mL of THF is then added dropwise and the reaction medium isstirred for 4 hours. After treatment with saturated ammonium chloridesolution, extraction with ethyl acetate, drying and evaporation of thesolvents from the organic phase, the residue obtained is purified bychromatography on a column of silica. A yellow oil is obtained (m=4.3 g;Y=66%).

j) Methyl(E)-5-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoate

4.3 g (7.1 mmol) of(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoicacid are dissolved in 70 mL of 2-butanone, and 1.1 g of potassiumcarbonate (7.8 mmol) and 2.2 mL of iodomethane (35 mmol) are added. Themedium is refluxed for 12 hours, cooled and filtered. The filtrate isconcentrated under reduced pressure and then purified by chromatographyon a column of silica. A yellow oil is obtained (m=4.34 g; Y=98%).

k)(E)-7-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

1.3 g (2.3 mmol) of methyl(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoateare dissolved in 20 mL of ethyl ether. 2.2 mL of 3.0 M ethylmagnesiumbromide solution (6.5 mmol) are then added dropwise and the reactionmedium is stirred at room temperature for 2 hours. After treatment withsaturated ammonium chloride solution, extraction with ethyl acetate andthen drying and evaporation of the solvents from the organic phase, theresidue obtained is purified by chromatography on a column of silica.After separation of the Z isomer from the E isomer, a colourless oil isobtained (m=440 mg; y=29%).

l)(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol

440 mg (0.7 mmol) of(E)-7-{4-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]cyclopenta-1,3-dienyl}-3-ethylnon-6-en-3-olare dissolved in 20 mL of THF. 2.0 mL (2.0 mmol) of 1.0 Mtetrabutylammonium fluoride solution are added and the reaction mediumis stirred at room temperature for 1 hour. After treatment with ammoniumchloride solution and extraction with ethyl acetate, the organic phasesare combined, dried and concentrated under reduced pressure. The residueis purified by chromatography on a column of silica (eluent: 80 ethylacetate/20 heptane). A white powder (m.p.: 82° C.) is obtained (m=248mg; Y=89%).

¹H NMR (DMSO): 0.82 (t, 6H, J=7.5 Hz); 1.07 (t, 3H, J=7.4 Hz); 1.36-1.46(m, 6H); 2.03 (s, 1H); 2.10-2.20 (m, 2H); 2.42-2.51 (m, 2H); 4.47 (d,2H, J=4.9 Hz); 4.56 (d, 2H, J=4.9 Hz); 4.99 (t, 1H, J=4.9 Hz); 5.15 (t,1H, J=4.9 Hz); 5.23 (s, 2H); 5.82 (t, 1H, J=7.3 Hz); 6.87-6.96 (m, 2H);7.08 (d, 2H, J=2.8 Hz); 7.28 (d, 1H, 8.3 Hz).

EXAMPLE 7(4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol

a) Ethyl(E)-3-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-2-thienyl)-2-pentenoate

4.1 mL (20 mmol) of triethyl phosphonoacetate are dissolved in 100 mL ofanhydrous THF and NaH (0.8 g, 20 mmol) is then added portionwise. Afterstirring for 30 minutes, a solution of 5.75 g (10.4 mmol) of1-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1-propanone(prepared in Example 6(h)) in 50 mL of anhydrous THF is added dropwiseand the reaction medium is heated for 14 hours at 50° C. After the usualtreatment and chromatography on silica gel (eluent: 90 heptane/10 ethylacetate), the desired product is separated from its Z isomer andobtained in the form of a colourless oil (m=3.18 g; Y=50%).

b)(E)-3-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-en-1-ol

3.18 g (5.2 mmol) of ethyl(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-2-pentenoatedissolved in 20 mL of ethyl ether are added dropwise to a suspension oflithium aluminium hydride (0.24 g, 6.3 mmol) in 50 mL of ether. Themedium is stirred at room temperature for 2 hours and then treatedsuccessively with 240 μL of water, 240 μL of 15% sodium hydroxide and720 μL of water. The medium is then filtered and the filtrate isconcentrated under reduced pressure. The desired product (m=2.92 g;Y=93%) is obtained in the form of a colourless oil.

c)(E)-3-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-2-thienyl}pent-2-enal

2.74 g (5.1 mmol) of(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-en-1-olare dissolved in 80 mL of dichloromethane and placed under a nitrogenatmosphere. 4.45 g (51 mmol) of manganese dioxide are added and themedium is stirred for 14 hours. After filtration and then evaporation, ayellow oil is obtained. The crude product (2.9 g) is the expectedaldehyde, obtained in a quantitative yield.

d) Ethyl(2E,4E)-5-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-2-thienyl}hepta-2,4-dienoate

In a manner similar to that of Example 7(a), by reaction of 2.9 g (5.1mmol) of(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-enalwith 1.5 mL (7.6 mmol) of triethyl phosphonoacetate, a single isomer isobtained. Ethyl(2E,4E)-5-{5-[3,4-bis(tert-butyldimethyl-silanyloxymethyl)phenoxymethyl]-2-thienyl}hepta-2,4-dienoateis isolated in the form of a yellow oil (m=2.17 g; Y=67%).

e)(4E,6E)-7-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol

An ethyllithium solution (1.5 M) is prepared by slow addition of asolution of ethyl bromide (11.2 mL, 150 mmol) in 50 mL of pentane to asuspension of lithium (2.75 g, 400 mmol) in 50 mL of pentane at 40° C.,followed by stirring at 40° C. for 12 hours. After cooling to roomtemperature, 23 mL (34 mmol) of this solution are added dropwise to asolution at 0° C. of ethyl(2E,4E)-5-{5-[3,4-bis(tert-butyldimethylsilanyl-oxymethyl)phenoxymethyl]-2-thienyl}hepta-2,4-dienoatein 50 mL of THF. The medium turns red and is stirred for 2 hours at 0°C. and then treated by addition of saturated ammonium chloride solution.After the usual treatment, the residue is purified by chromatography onsilica gel (eluent: 95 heptane/5 ethyl acetate). The desired product isobtained in the form of a yellow oil (m=0.85 g, Y=38%).

f)(4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol

850 mg (1.3 mmol) of(4E,6E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-olare dissolved in 20 mL of anhydrous THF. 3.9 mL (3.9 mmol) of 1 Mtetrabutylammonium fluoride solution are then added and the medium isstirred for 4 hours. After the usual treatment, the residue is purifiedby chromatography on silica gel (eluent: 2 heptane/8 ethyl acetate).(4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-olis obtained in the form of a yellow oil (m=340 mg; Y=63%).

¹H NMR (DMSO): 0.74 (t, 6H, J=7.5 Hz); 1.13 (t, 3H, J=7.4 Hz); 1.36-1.45(m, 4H); 2.26 (t, 1H, J=6.9 Hz); 2.46-2.53 (m, 2H); 4.38 (d, 2H, J=4.8Hz); 4.47 (d, 2H, J=4.8 Hz); 4.90 (t, 1H, J=4.8 Hz); 5.05 (t, 1H, J=4.8Hz); 5.16 (s, 2H); 5.76 (d, 1H, J=13.8 Hz); 6.36-6.47 (m, 2H); 6.79-6.83(m, 1H); 6.98-7.04 (m, 3H); 7.20 (d, 1H, J=8.3 Hz).

EXAMPLE 8(E)-7-{5-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

a) Dimethyl4-{(E)-2-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienyl]vinyl}phthalate

18.5 g (53.7 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)phthalate and9.5 g (44.7 mmol) of5-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-2-carbaldehyde (described inExample 6(b)) are dissolved in 200 mL of anhydrous THF. 6.02 g (53.7mmol) of potassium tert-butoxide are added and the mixture is stirredfor 24 h. After the usual treatment and chromatography on silica gel(eluent: 8 heptane/2 ethyl acetate), the desired product is obtained inthe form of a yellow oil (m=9.53 g, Y=53%).

b) Dimethyl4-{2-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}phthalate

9.3 g (23 mmol) of dimethyl4-{(E)-2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]vinyl}phthalate aredissolved in 150 mL of dioxane and 1 mL of triethylamine is then added.The mixture is degassed using a stream of nitrogen and 9.3 g of 5%palladium-on-charcoal are then added to the reaction medium. A positivepressure of hydrogen is maintained in the reaction medium for 5 hours,with heating at 80° C. After cooling and then filtration through Celiteand evaporation, the desired product is obtained in the form of a yellowoil (m=9.4 g; Y=100%).

c)4-{2-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}-2-hydroxymethylphenyl)methanolIn a manner similar to that of Example 6(f), by reaction of 9.3 g (23mmol) of dimethyl4-{2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}phthalate with 2.2g (58 mmol) of lithium aluminium hydride, the desired product isobtained in the form of a colourless oil (m=8.7 g; Y=100%).

d) 1-{5-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl}-1-propanone

In a manner similar to that of Example 6(g), by reaction of 8.7 g (23mmol) of(4-{2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}-2-hydroxymethylphenyl)methanolwith a solution of para-toluenesulphonic acid in an acetone/watermixture, the desired product is obtained in the form of a white powder(m=5.41 g; Y=71%).

e)1-{5-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-1-propanone

In a manner similar to that of Example 6(h), by reaction of 5.4 g (17.7mmol) of1-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1-propanone with3.37 g (49 mmol) of imidazole and 5.86 g (39 mmol) oftert-butyldimethylchlorosilane, the desired product is obtained in theform of a colourless oil (m=9.4 g; Y=100%).

f)(E)-5-{5-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-4-heptenoicAcid

In a manner similar to that of Example 6(i), by reaction of 5.08 g (9.5mmol) of1-{5-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-1-propanonewith 6.1 g (14 mmol) of (3-carboxypropyl)triphenylphosphonium bromideand 3.1 g (28 mmol) of potassium tert-butoxide, the desired product isobtained in the form of a yellow oil (m=2.7 g; Y=48%).

g) Methyl(E)-5-{5-[2-(3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl)ethyl]-2-thienyl}-4-heptenoate

In a manner similar to that of Example 6(j), by reaction of 2.7 g (4.5mmol) of(E)-5-15-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-4-heptenoicacid with 680 mg (4.9 mmol) of potassium carbonate and 1.38 mL (22.6mmol) of methyl iodide, the desired product is obtained in the form of ayellow oil (m=1.79 g; Y=64%).

h)(E)-7-{5-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(k), by reaction of 1.79 g (2.9mmol) of methyl(E)-5-{5-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)-ethyl]-2-thienyl}-4-heptenoatewith 2.9 mL (8.7 mmol) of 3.0 M ethylmagnesium bromide, the desiredproduct is obtained in the form of a colourless oil (m=710 mg; Y=38%).

i)(E)-7-{5-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(l), by reaction of 710 mg (1.1mmol) of(E)-7-{5-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-olwith 3.3 mL (3.3 mmol) of 1.0 M tetrabutylammonium fluoride solution,the desired product is obtained in the form of a white powder (m.p.=77°C.; m=380 mg; Y=83%).

¹H NMR (DMSO): 0.74 (t, 6H, J=7.5 Hz); 0.97 (t, 3H, J=7.4 Hz); 1.26-1.35(m, 6H); 1.99-2.09 (m, 2H); 2.34 (q, 2H, J=7.4 Hz); 2.80-2.86 (m, 2H);2.92-2.98 (m, 2H); 3.86 (s, 1H); 4.43-4.47 (m, 4H); 4.95 (t, 1H, J=4.7Hz); 5.00 (t, 1H, J=4.7 Hz); 5.63 (t, 1H, J=7.3 Hz); 6.65 (d, 1H, J=3.4Hz); 6.75 (d, 1H, J=3.4 Hz); 7.04 (d, 1H, J=7.65 Hz); 7.20-7.22 (m, 2H).

EXAMPLE 9(E)-7-[4-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol

a) 1-(4-Bromo-2-thienyl)-1-propanol

30 g (157 mmol) of 4-bromo-2-thiophenecarboxaldehyde are dissolved in200 mL of anhydrous THF. 104 mL (312 mmol) of 3.0 M ethylmagnesiumbromide are added slowly and the medium is stirred for 2 hours at roomtemperature. After the usual treatment, an orange-coloured oil isobtained (m=33.5 g; Y=96%).

b) 1-(4-Bromo-2-thienyl)-1-propanone

33.5 g (151 mmol) of 1-(4-bromo-2-thienyl)-1-propanol are dissolved in400 mL of dichloromethane. 130 g (1.5 mol) of manganese dioxide are thenadded portionwise and the medium is stirred at room temperature for 24hours. After filtration through Celite and then concentration andchromatography on silica gel (eluent: 9 heptane/1 ethyl acetate), thedesired product is obtained in the form of white crystals (m=26.6 g;Y=80%).

c) (E)-5-(4-Bromo-2-thienyl)-4-heptenoic Acid

In a manner similar to that of Example 6(i), by reaction of 16 g (73mmol) of 1-(4-bromo-2-thienyl)-1-propanone with 47 g (109 mmol) of(3-carboxypropyl)triphenylphosphonium bromide and 24.6 g (219 mmol) ofpotassium tert-butoxide, the desired product is obtained in the form ofan orange-coloured solid (m=16.7 g; Y=80%).

d) Ethyl (E)-5-(4-Bromo-2-thienyl)-4-heptenoate

16.6 g (57 mmol) of (E)-5-(4-bromo-2-thienyl)-4-heptenoic acid aredissolved in 150 mL of absolute ethanol and 1 mL of concentratedsulphuric acid is added. The mixture is refluxed for 2 hours and thencooled. After the usual treatment and chromatography on silica gel, thedesired product is obtained in the form of a yellow oil (m=14.1 g;Y=77%).

e) (E)-7-(4-Bromo-2-thienyl)-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(k), by reaction of 14.1 g (44.4mmol) of ethyl (E)-5-(4-bromo-2-thienyl)-4-heptenoate with 60 mL (180mmol) of 3.0 M ethylmagnesium bromide, the desired product is obtainedin the form of a yellow oil (m=12.8 mg; Y=87%).

f) [(E)-5-(4-Bromo-2-thienyl)-1,1-diethylhept-4-enyloxy]triethylsilane

11.8 g (35.6 mmol) of (E)-7-(4-bromo-2-thienyl)-3-ethylnon-6-en-3-ol aredissolved in 150 mL of dichloromethane. 130 mg (1.1 mmol) ofdimethylaminopyridine and 14.9 mL (107 mmol) of triethylamine are added.The reaction medium is cooled to 0° C. and 12.1 mL (53.4 mmol) oftriethylsilyl trifluoromethanesulphonate are added dropwise. The mediumis warmed to room temperature and stirred for 15 minutes, after which itis poured into 150 mL of water and extracted with dichloromethane. Afterchromatography on silica gel (eluent: heptane), the desired product isobtained in the form of a colourless oil (m=15 g; Y=100%).

g)5-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)thiophene-3-carbaldehyde

11 g (24.7 mmol) of[(E)-5-(4-bromo-2-thienyl)-1,1-diethylhept-4-enyloxy]triethylsilane aredissolved in 100 mL of anhydrous THF and the mixture is cooled to −78°C. 10.9 mL (27 mmol) of 2.5 M butyllithium are added slowly and themixture is stirred for 15 minutes. 2.1 mL (27 mmol) of dimethylformamideare then added and the medium is stirred for 30 minutes and then pouredinto aqueous ammonium chloride solution. After extraction with ethylacetate and chromatography on silica gel (eluent: 9 heptane/1 ethylacetate), the product is obtained in the form of a colourless oil (m=4g; Y=41%).

h)[5-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienyl]methanol

4 g (9.9 mmol) of5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)thiophene-3-carbaldehydeare dissolved in 50 mL of THF and 50 mL of methanol. 1 g (26 mmol) ofsodium borohydride is then added portionwise. The reaction medium isstirred for 1 hour and then poured into 100 mL of water. Afterpurification by chromatography on silica gel, the desired product isobtained in the form of a colourless oil (m=4 g; Y=100%).

i) Dimethyl4-[5-((E)-1,5-Diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienylmethoxy]phthalate

3.9 g (9.8 mmol) of[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienyl]methanolare dissolved in 100 mL of dichloromethane and the mixture is cooled to0° C. 2 mL (15 mmol) of triethylamine are added, followed by 840 μL(10.7 mmol) of methanesulphonyl chloride. After stirring for 30 minutes,the medium is treated with ammonium chloride solution. The crude residueobtained is then dissolved in 100 mL of 2-butanone. 100 mg (0.7 mmol) ofsodium iodide, 1.6 g (11.6 mmol) of potassium carbonate and 2 g (10mmol) of dimethyl 4-hydroxyphthalate are added to this solution. Thereaction medium is refluxed for 15 hours and then cooled and filteredthrough Celite. The residue obtained is purified by chromatography on acolumn of silica (eluent: 93 heptane/7 ethyl acetate). The desiredproduct is obtained in the form of a colourless oil (m=1.7 g; Y=30%).

j) Dimethyl4-[5-((E)-1,5-Diethyl-5-hydroxyhept-1-enyl)-3-thienylmethoxy]phthalate

1.7 g (2.9 mmol) of dimethyl4-[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienylmethoxy]phthalateare dissolved in 50 mL of anhydrous THF. 3.5 mL (3.5 mmol) oftetrabutylammonium fluoride (1.0 M in THF) are added and the medium isstirred at 60° C. for 3 hours. After the usual treatment andpurification on silica gel (eluent: 70 heptane/30 ethyl acetate), thedesired product is obtained in the form of a yellow oil (m=710 mg;Y=51%).

k)(E)-7-[4-(3,4-bis-Hydroxymethyl-phenoxymethyl)2-thienyl]-3-ethylnon-6-en-3-ol

480 mg (1.1 mmol) of dimethyl4-[5-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-3-thienylmethoxy]phthalateare dissolved in 10 mL of ethyl ether. This solution is added to asuspension of 130 mg (3.4 mmol) of lithium aluminium hydride and thereaction medium is stirred for 15 minutes. The reaction medium is thentreated by successive addition of 130 μL of water, 130 μL of 15% sodiumhydroxide and 400 μL of water. After filtration and chromatography onsilica gel (eluent: 2 heptane/8 ethyl acetate), the desired product isobtained in the form of white crystals (m.p.=63-64° C.; m=380 mg;Y=90%).

¹H NMR (DMSO): 0.63 (t, 6H, J=7.5 Hz); 0.87 (t, 3H, J=7.4 Hz); 1.16-1.24(m, 6H); 1.90-2.00 (m, 2H); 2.26 (q, 2H, J=7.4 Hz); 3.76 (s, 1H); 4.27(d, 2H, J=5.3 Hz); 4.36 (d, 2H, J=5.3 Hz); 4.77 (t, 1H, J=5.3 Hz); 4.94(t, 1H, J=5.3 Hz); 5.03 (s, 2H); 5.62 (t, 1H, J=7.3 Hz); 6.67-6.76 (m,2H); 6.88 (d, 2H, J=2.5 Hz); 7.12 (d, 1H, J=13.8 Hz).

EXAMPLE 10(E)-7-[4-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl)-3-ethylnon-6-en-3-ol

a) 2-(4-Bromo-2-thienyl)-2-ethyl-[1,3]dioxolane

10.5 g (48 mmol) of 1-(4-bromo-2-thienyl)-1-propanone (described inExample 9(b)) are dissolved in 150 mL of toluene. 13.4 mL (239 mmol) ofethylene glycol and 450 mg (2.4 mmol) of para-toluenesulphonic acid areadded. The assembly is equipped with Dean-Stark distillation apparatusand the reaction medium is heated to 130° C. After refluxing for 24hours, the mixture is treated with sodium bicarbonate solution andextracted with ethyl acetate. The crude product obtained is the desiredproduct (m=12.2 g; Y=100%).

b) 2-(2-Ethyl-[1,3]dioxolan-2-yl)thiophene-4-carbaldehyde

In a manner similar to that of Example 9(g), by reaction of 12 g (45.6mmol) of 2-(4-bromo-2-thienyl)-2-ethyl-[1,3]dioxolane with 20 mL (50mmol) of 2.5 M butyllithium and 3.9 mL (50 mmol) of dimethylformamide,the desired product is obtained in the form of a yellow oil (m=4.6 g,Y=48%).

c) Dimethyl4-{(E)-2-[2-(2-Ethyl-[1,3]dioxolan-2-yl)-4-thienyl]vinyl}phthalate

In a manner similar to that of Example 8(a), by reaction of 4.6 g (21.6mmol) of 2-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-4-carbaldehyde with 8.9g (26 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)-phthalate and 2.9 g(26 mmol) of potassium tert-butoxide, the desired product is obtained inthe form of a yellow oil (m=7 g; Y=87%).

d) Dimethyl4-{2-[2-(2-Ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}phthalate

In a manner similar to that of Example 8(b), by reaction of 7 g (19mmol) of dimethyl4-{(E)-2-[2-(2-ethyl-[1,3]dioxolan-4-yl)-3-thienyl]vinyl}phthalate with7 g of 5% palladium-on-charcoal, the desired product is obtained in theform of a colourless oil (m=6.7 g; Y=95%).

e)(4-{2-[2-(2-Ethyl-[1,3]dioxolan-2-yl)-4-thienyl]-ethyl}-2-hydroxymethylphenyl)methanol

In a manner similar to that of Example 6(f), by reaction of 6.7 g (18mmol) of dimethyl4-{2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}phthalate with 1.6g (43 mmol) of lithium aluminium hydride, the desired product isobtained in the form of a colourless oil (m=5.3 g; Y=85%).

f) 1-{4-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl}-1-propanone

In a manner similar to that of Example 6(g), by reaction of 5.3 g (15mmol) of(4-{2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}-2-hydroxymethyl-phenyl)methanolwith a solution of para-toluenesulphonic acid in an acetone/watermixture, the desired product is obtained in the form of a white powder(m=4 g; Y=86%).

g)1-{4-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-1-propanone

In a manner similar to that of Example 6(h), by reaction of 3.8 g (12mmol) of1-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1-propanone with2.1 g (31 mmol) of imidazole and 4.1 g (27.5 mmol) oftert-butyldimethylchlorosilane, the desired product is obtained in theform of a colourless oil (m=6.8 g; Y=100%).

h)(E)-5-{4-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-4-heptenoicAcid

In a manner similar to that of Example 6(i), by reaction of 3 g (5.6mmol) of1-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-1-propanonewith 3.6 g (8.4 mmol) of (3-carboxy-propyl)triphenylphosphonium bromideand 1.9 g (17 mmol) of potassium tert-butoxide, the desired product isobtained in the form of a yellow oil (m=1.7 g, Y=50%).

i) Methyl(E)-5-{4-[2-(3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl)ethyl]-2-thienyl}-4-heptenoate

In a manner similar to that of Example 6(j), by reaction of 1.6 g (2.6mmol) of(E)-5-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-4-heptenoicacid with 400 mg (2.9 mmol) of potassium carbonate and 810 μL (13 mmol)of methyl iodide, the desired product is obtained in the form of ayellow oil (m=1.4 g; Y=86%).

j)(E)-7-{4-[2-(3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(k), by reaction of 1.4 g (2.3mmol) of methyl(E)-5-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)-ethyl]-2-thienyl}-4-heptenoatewith 3 mL (9 mmol) of 3.0 M ethylmagnesium bromide, the desired productis obtained in the form of a colourless oil (m=1 g, Y=69%).

k)(E)-7-{4-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(l), by reaction of 1 g (1.55mmol) of(E)-7-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-olwith 3.7 mL (3.7 mmol) of 1.0 M tetrabutylammonium fluoride solution,the desired product is obtained in the form of white crystals(m.p.=85-86° C.; m=580 mg; Y=90%).

¹H NMR (DMSO): 0.89 (t, 6H, J=7.6 Hz); 1.12 (t, 3H, J=7.4 Hz); 1.42-1.51(m, 6H); 2.15-2.24 (m, 2H); 2.50 (q, 2H, J=7.4 Hz); 2.96-3.01 (m, 2H);3.08-3.14 (m, 2H); 4.00 (s, 1H); 4.58-4.62 (m, 4H); 5.11 (t, 1H, J=4.7Hz); 5.15 (t, 1H, J=4.8 Hz); 5.79 (t, 1H, J=7.4 Hz); 6.81 (d, 1H, J=3.5Hz); 6.90 (d, 1H, J=3.5 Hz); 7.20 (d, 1H, J=7.7 Hz); 7.35-7.38 (m, 2H).

EXAMPLE 11(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethyl-4,4-dimethylnon-6-en-3-ol

a) (3-Bromo-5-thienyl)methanol

In a manner similar to that of Example 9(h), by reaction of 20.5 g (107mmol) of 3-bromothiophene-3-carboxaldehyde with 4 g (110 mmol) of sodiumborohydride, the desired product is obtained in the form of a yellow oil(m=20 g; Y=100%).

b) Dimethyl 3-(3-Bromo-5-thienylmethoxy)phthalate

In a manner similar to that of Example 9(i), by reaction of 20 g (103mmol) of (3-bromo-5-thienyl)methanol with 21.6 mL (155 mmol) oftriethylamine and 8.8 mL (114 mmol) of methanesulphonyl chloride,followed by 500 mg (3.5 mmol) of sodium iodide, 14.3 g (103 mmol) ofpotassium carbonate and 21.7 g (103 mmol) of dimethyl4-hydroxyphthalate, the desired product is obtained in the form oforange-coloured crystals (m.p.=65° C.; m=27 g; Y=74%).

c) [5-(3-Bromo-5-thienylmethoxy)-2-hydroxymethyl-phenyl]methanol

27 g (76 mmol) of dimethyl 4-(3-bromo-5-thienylmethoxy)phthalate aredissolved in 200 mL of anhydrous THF. This solution is added dropwise toa suspension of 4 g (183 mmol) of lithium borohydride in 50 mL of THF.The reaction medium is refluxed for 24 h and then cooled and poured onto200 g of ice. After extraction with ether and then chromatography on acolumn of silica (eluent: 5 heptane/5 ethyl acetate), the desiredproduct is obtained in the form of a yellow oil (m=22.1 g; Y=88%).

d)5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)-phenoxymethyl]-3-bromothiophene

In a manner similar to that of Example 6(h), by reaction of 22 g (67mmol) of [5-(3-bromo-5-thienylmethoxy)-2-hydroxymethylphenyl]methanolwith 11.4 g (167 mmol) of imidazole and 22 g (147 mmol) oftert-butyldimethylchlorosilane, the desired product is obtained in theform of a colourless oil (m=34 g, y=91%).

e)5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)-phenoxymethyl]thiophene-3-carbaldehyde

In a manner similar to that of Example 9(g), by reaction of 34 g (61mmol) of5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-bromothiophenewith 27 mL (67 mmol) of 2.5 M butyllithium and 5.2 mL (67 mmol) ofdimethylformamide, the crude product obtained (33.8 g; Y=99%) is in theform of a brown oil.

f)1-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)-phenoxymethyl]-3-thienyl}-1-propanol

In a manner similar to that of Example 9(a), by reaction of 33 g (65mmol) of5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]thiophene-3-carbaldehydewith 44 mL (130 mmol) of ethylmagnesium bromide, the product is obtainedin the form of a yellow oil (m=28.4 g; Y=88%).

g)1-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)-phenoxymethyl]-3-thienyl}-1-propanone

In a manner similar to that of Example 9(b), by reaction of 28 g (52mmol) of1{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-1-propanolwith 45 g (520 mmol) of manganese dioxide, the desired product isobtained in the form of an orange-coloured oil (m=26 g; Y=93%).

h)(E)-5-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-3-thienyl}-4-heptenoicAcid

In a manner similar to that of Example 6(i), by reaction of 10 g (18.7mmol) of1-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-1-propanonewith 12 g (28 mmol) of (3-carboxy-propyl)triphenylphosphonium bromideand 6.3 g (56 mmol) of potassium tert-butoxide, the desired product isobtained in the form of a brown oil (m=5.4 g; Y=48%).

i) Methyl(E)-5-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-3-thienyl}-4-heptenoate

In a manner similar to that of Example 6(j), by reaction of 5.4 g (8.9mmol) of(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-4-heptenoicacid with 1.3 g (9.4 mmol) of potassium carbonate and 2.7 mL (44 mmol)of methyl iodide, the desired product is obtained in the form of acolourless oil (m=3 g; Y=54%).

j) Methyl(E)-5-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-2,2-dimethyl-4-heptenoate

1.3 g (2.1 mmol) of methyl(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-4-heptenoateare dissolved in 20 mL of THF. This solution is added to a solution of3.2 mmol of lithium diisopropylamide in 10 mL of THF at −78° C. After 10minutes, 390 μL (6.2 mmol) of methyl iodide are added and the reactionmedium is warmed to room temperature and then stirred for 12 h. Afterthe usual treatment, the crude residue obtained is subjected a secondtime to the same operating conditions. After chromatography on silicagel (eluent: 97 heptane/3 ethyl acetate), the desired product isobtained in the form of a colourless oil (m=680 mg; Y=50%).

k)(E)-7-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-3-thienyl}-3-ethyl-4,4-dimethylnon-6-en-3-ol

In a manner similar to that of Example 6(k), by reaction of 670 mg (1mmol) of methyl(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-2,2-dimethyl-4-heptenoatewith 1.4 mL (4.2 mmol) of ethylmagnesium bromide, the desired product isobtained in the form of a colourless oil (m=310 mg; Y=44%).

l)(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethyl-4,4-dimethylnon-6-en-3-ol

In a manner similar to that of Example 6(l), by reaction of 310 mg (0.46mmol) of(E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethyl-4,4-dimethylnon-6-en-3-olwith 1.1 mL (1.1 mmol) of 1.0 M tetrabutylammonium bromide, the desiredproduct is obtained in the form of a colourless oil (m=200 mg; Y=98%).

¹H NMR (CDCl₃): 0.93-1.08 (m, 12H); 1.22 (t, 3H, J=8.6 Hz); 1.62 (q, 4H,J=8.5 Hz); 2.29 (d, 2H, J=9.6 Hz); 2.48 (q, 2H, J=8.6 Hz); 4.71 (s, 2H);4.73 (s, 2H); 5.20 (s, 2H); 5.94 (t, 1H, J=9.6 Hz); 6.90-6.95 (m, 1H);7.04 (d, 1H, J=3.9 Hz); 7.09 (d, 1H, J=3.8 Hz); 7.22-7.31 (m, 2H).

EXAMPLE 12(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnon-6-en-3-ol

a)(E)-7-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-3-thienyl}-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(k), by reaction of 1 g (1.6mmol) of methyl(E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-4-heptenoate(described in Example 11(i)) with 2.1 mL (6.3 mmol) of 3.0 Methylmagnesium bromide, the desired product is obtained in the form of acolourless oil (m=1 g; Y=96%).

b)(E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnon-6-en-3-ol

In a manner similar to that of Example 6(l), by reaction of 1 g (1.5mmol) of(E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethylnon-6-en-3-olwith 3.7 mL (3.7 mmol) of 1.0 M tetrabutylammonium bromide, the desiredproduct is obtained in the form of white crystals (m.p.=73-74° C.; m=480mg; Y=74%).

¹H NMR (DMSO): 0.65 (t, 6H, J=7.6 Hz); 0.84 (t, 3H, J=7.5 Hz); 1.18-1.28(m, 6H); 1.91-2.00 (m, 2H); 2.25 (q, 2H, J=7.4 Hz); 3.76 (s, 1H); 4.28(d, 2H, J=4.9 Hz); 4.37 (d, 2H, J=4.9 Hz); 4.79 (t, 1H, J=5.0 Hz); 4.96(t, 1H, J=5.0 Hz); 5.06 (s, 2H); 5.67 (t, 1H, J=7.3 Hz); 6.69-6.74 (m,1H); 6.90 (d, 1H, J=2.4 Hz); 7.10 (d, 1H, J=8.3 Hz); 7.17-7.20 (m, 2H).

EXAMPLE 13(3E,5E)-6-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

a)2-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-5-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)thiophene

770 mg (11.7 mmol) of zinc, 3.09 g (11.7 mmol) of triphenylphosphine and3.9 g (11.7 mmol) of carbon tetrabromide are stirred for 30 minutes atroom temperature in 150 mol of dichloromethane. A solution of 3.3 g (5.9mmol) of(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-enal(described in Example 7(c)) in 30 mL of dichloromethane is then addeddropwise. After stirring for 1 h at room temperature the reaction mediumis treated with water and extracted with dichloromethane. Afterpurification on silica gel (eluent: 95 heptane/5 ethyl acetate), thedesired product is obtained in the form of a brown oil (m=3.9 g; Y=93%).

b)2-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-5-((E)-1-ethylbut-1-en-3-ynyl)-thiophene

3.9 g (5.4 mmol) of2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-5-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)thiopheneare dissolved in 100 mL of THF and the mixture is cooled to −78° C. 4.4mL (11 mmol) of 2.5 M butyllithium are added slowly and the reactionmedium is stirred at the same temperature for 1 hour. After the usualtreatment and chromatography on silica gel (eluent: 96 heptane/4 ethylacetate), the desired product is obtained in the form of a brown oil.

c)(E)-6-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol

1.7 g (3 mmol) of2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-5-((E)-1-ethyl-but-1-en-3-ynyl)thiopheneare dissolved in 50 mL of THF and the mixture is cooled to −78° C. 1.3mL (3.3 mmol) of 2.5 M butyllithium are then added. After stirring for15 minutes at the same temperature, a gentle flow of hexafluoroacetone(gas) is introduced into the reaction medium. After reaction for 20minutes at −78° C., the flow of gas is stopped and the reaction mediumis treated in the usual manner. The residue obtained is purified bychromatography on silica gel. The desired product is obtained in theform of a yellow oil (1 g).

d)(3E,5E)-6-{5-[3,4-bis(tert-Butyldimethylsilanyl-oxymethyl)phenoxymethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

1 g (1.3 mmol) of(E)-6-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1,1,1,-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-olis dissolved in 10 mL of THF and then added to a suspension of 160 mg(4.2 mmol) of lithium aluminium hydride and 450 mg (8.4 mmol) of sodiummethoxide in 20 mL of THF. After stirring at reflux for 2 hours, themedium is cooled and then treated with 200 μL of water, 200 μL of 15%sodium hydroxide and 600 μL of water. After filtration, the residue ispurified by chromatography on silica gel (eluent: 95 heptane/5 ethylacetate). The desired product is obtained in the form of a yellow oil(210 mg).

e)(3E,5E)-6-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

In a manner similar to that of Example 6(l), by reaction of 200 mg of(3E,5E)-6-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-olwith 700 μL (0.7 mmol) of 1.0 M tetrabutylammonium bromide, the desiredproduct is obtained in the form of white crystals (m.p.=113-114° C.;m=70 mg).

¹H NMR (DMSO): 1.12 (t, 3H, J=7.5 Hz); 2.71 (q, 2H, J=7.5 Hz); 4.48 (d,2H, J=5.1 Hz); 4.57 (d, 2H, J=5.1 Hz); 4.99 (t, 1H, J=5.1 Hz); 5.15 (t,1H, J=5.1 Hz); 5.29 (s, 2H); 5.53 (d, 1H, J=11.6 Hz); 6.89-7.04 (m, 2H);7.10-7.35 (m, 5H); 8.50 (s, 1H).

EXAMPLE 14(4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-ol

a) Ethyl(E)-3-{5-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenoxymethyl]-3-thienyl}-2-pentenoate

In a manner similar to that of Example 7(a), by reaction of 6 g (11.2mmol) of1-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-1-propanone(prepared in Example 11(g)) with 4.4 mL (22.4 mol) of triethylphosphonoacetate and 0.9 g (22.4 mmol) of sodium hydride, the desiredproduct is separated from its Z isomer and obtained in the form of acolourless oil (m=5.3 g; Y=78%).

b)(E)-3-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-3-thienyl}pent-2-en-1-ol

In a manner similar to that of Example 7(b), by reaction of 2.3 g (3.8mmol) of ethyl(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-2-pentenoatewith 180 mg (4.7 mmol) of lithium aluminium hydride, the desired product(m=2.1 g; Y=100%) is obtained in the form of a colourless oil.

c)(E)-3-{5-[3,4-bis(tert-Butyldimethylsilanyloxy-methyl)phenoxymethyl]-3-thienyl}pent-2-enal

In a manner similar to that of Example 7(c), by reaction of 2.1 g (3.7mmol) of(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}pent-2-en-1-olwith 4.9 g (56 mmol) of manganese dioxide, the crude product (1.8 g) isthe expected aldehyde, obtained in a yield of 86%.

d) Ethyl(2E,4E)-5-{5-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}hepta-2,4-dienoate

In a manner similar to that of Example 7(a), by reaction of 1.8 g (3.2mmol) of(E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}pent-2-enalwith 0.96 mL (4.8 mmol) of triethyl phosphonoacetate, a single isomer isobtained: ethyl(2E,4E)-5-{5-[3,4-bis(tert-butyldimethyl-silanyloxymethyl)phenoxymethyl]-3-thienyl}hepta-2,4-dienoateis isolated in the form of a yellow oil (m=2 g; Y=100%).

e)(4E,6E)-7-{5-[3,4-bis(tert-Butyldimethylsilanyl-oxymethyl)phenoxymethyl]-3-thienyl}-3-ethylnona-4,6-dien-3-ol

In a manner similar to that of Example 7(e), by reaction of 1.6 g (2.5mmol) of ethyl(2E,4E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}hepta-2,4-dienoatewith 17 mL of ethyllithium solution (1.5 M), the desired product isobtained in the form of a yellow oil (m=160 mg, Y=10%).

f)(4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-ol

In a manner similar to that of Example 7(f), by reaction of 155 mg (0.24mmol) of(4E,6E)-7-{5-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethylnona-4,6-dien-3-olwith 0.58 mL (0.58 mmol) of 1 M tetrabutylammonium fluoride solution,(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-olis obtained in the form of a yellow oil (m=80 mg; Y=80%).

¹H NMR (DMSO): 0.83 (t, J=7.5 Hz, 6H); 1.08 (t, J=7.6 Hz, 3H); 1.50 (q,J=7.5 Hz, 4H); 2.54-2.60 (m, 2H); 4.33 (s, 1H); 4.48 (d, J=5 Hz, 2H);4.57 (d, J=5 Hz, 2H); 4.98 (t, J=5 Hz, 1H); 5.15 (t, J=5 Hz, 1H); 5.27(s, 2H); 5.80-5.84 (m, 1H); 6.55-6.59 (m, 2H); 6.91 (dd, J₁=2.6 Hz,J₂=8.3 Hz, 1H); 7.10 (d, J=2.6 Hz, 1H); 7.29 (d, J=8.2 Hz, 1H); 7.49 (s,2H).

EXAMPLE 15(4E,6E)-7-{4-[2-(3,4-bis-Hydroxymethyl-phenyl)ethyl]-thiopen-2-yl}-3-ethylnona-4,6-dien-3-ol

a) Ethyl(E)-3-(4-{2-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)-2-pentenoate

In a manner similar to that of Example 7(a), by reaction of 3.6 g (6.7mmol) of(E)-1-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-1-propanone(prepared in Example 10(g)) with 2.7 mL (13.5 mmol) of triethylphosphonoacetate and 540 mg (13.5 mmol) of sodium hydride, the desiredproduct is separated from its Z isomer and obtained in the form of acolourless oil (m=3.5 g; Y=86%).

b)(E)-3-(4-{2-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)pent-2-en-1-ol

In a manner similar to that of Example 7(b), by reaction of 2.3 g (3.8mmol) of ethyl(E)-3-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-2-thienyl)-2-pentenoatewith 180 mg (4.7 mmol) of lithium aluminium hydride, the desired product(m=2.1 g; Y=100%) is obtained in the form of a colourless oil.

c)(E)-3-(4-{2-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)pent-2-enal

In a manner similar to that of Example 7(c), by reaction of 2.0 g (3.6mmol) of(E)-3-(4-{2-[3,4-bis(tert-Butyldimethylsilanyloxymethyl)phenyl]ethyl}-2-thienyl)pent-2-en-1-olwith 4.9 g (56 mmol) of manganese dioxide, the crude product (2.0 g) isthe expected aldehyde, obtained in quantitative yield.

d) Ethyl(2E,4E)-5-(4-{2-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)hepta-2,4-dienoate

In a manner similar to that of Example 7(d), by reaction of 2 g (3.6mmol) of(E)-3-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-2-thienyl)pent-2-enalwith 1.1 mL (5.4 mmol) of triethyl phosphonoacetate, a single isomer isobtained: ethyl(2E,4E)-5-(4-{2-[3,4-bis(tert-butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)hepta-2,4-dienoateis isolated in the form of a yellow oil (m=1.9 g; Y=85%).

e)(4E,6E)-7-(4-{2-[3,4-bis(tert-Butyldimethyl-silanyloxymethyl)phenyl]ethyl}-2-thienyl)-3-ethyl-nona-4,6-dien-3-ol

In a manner similar to that of Example 7(e), by reaction of 1.9 g (3mmol) of ethyl(2E,4E)-5-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]-ethyl}-2-thienyl)hepta-2,4-dienoatewith 20 mL of ethyllithium solution (1.5 M), the desired product isobtained in the form of a yellow oil (m=448 mg, Y=24%).

f)(4E,6E)-7-(4-{2-[3,4-bis-Hydroxymethyl-phenyl]-ethyl}-2-thienyl)-3-ethylnona-4,6-dien-3-ol

In a manner similar to that of Example 7(f), by reaction of 440 mg (0.68mmol) of(4E,6E)-7-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-2-thienyl)-3-ethylnona-4,6-dien-3-olwith 1.5 mL (1.5 mmol) of 1 M tetrabutylammonium fluoride solution,(4E,6E)-7-(4-{2-[3,4-bis-hydroxymethyl-phenyl]ethyl}-2-thienyl)-3-ethylnona-4,6-dien-3-olis obtained in the form of a yellow oil (m=200 mg; Y=71%).

¹H NMR (DMSO): 0.57 (t, J=7.5 Hz, 6H); 0.88 (t, J=7.6 Hz, 3H); 1.24 (q,J=7.5 Hz, 6H); 2.29-2.34 (m, 2H); 2.66-2.72 (m, 2H); 2.79-2.85 (m, 2H);4.07 (s, 1H); 4.27-4.31 (m, 4H); 4.79 (t, J=5 Hz, 1H); 4.83 (t, J=5 Hz,1H); 5.54 (d, J=14.7 Hz, 1H); 6.13 (d, J=11.1 Hz, 1H); 6.28 (dd, J₁=11.1Hz, J₂=14.7 Hz, 1H); 6.54 (d, J=3.6 Hz, 1H); 6.72 (d, J=3.6 Hz, 1H);6.88 (dd, J₁=1.4 Hz, J₂=6.3 Hz, 1H); 7.05-7.07 (m, 2H).

EXAMPLE 16 Formulation Examples

1) Oral Route

(a) The composition below is prepared in the form of a 0.2 g tablet:

Compound of Example 1 0.005 g Pregelatinized starch 0.065 gMicrocrystalline cellulose 0.075 g Lactose 0.050 g Magnesium stearate0.005 g

For the treatment of ichthyosis, 1 to 3 tablets per day are administeredto an adult individual for 1 to 12 months depending on the severity ofthe case treated.

(b) A drinkable suspension, intended to be packaged in 5 mL ampules, isprepared:

Compound of Example 2 0.050 mg Glycerol 0.500 g 70% sorbitol 0.500 gSodium saccharinate 0.010 9 Methyl para-hydroxybenzoate 0.040 gFlavouring q.s. Purified water q.s. 5 mL

For the treatment of acne, 1 ampule per day is administered to an adultindividual for 1 to 12 months depending on the severity of the casetreated.

(c) The formulation below intended to be packaged in gel capsules isprepared:

Compound of Example 4 0.0001 mg Corn starch 0.060 g Lactose q.s. 0.300 g

The gel capsules used consist of gelatin, titanium oxide and apreserving agent.

In the treatment of psoriasis, 1 gel capsule per day is administered toan adult individual for 1 to 12 months.

(d) The formulation below intended to be packed in gel capsules isprepared:

Compound of Example 5 0.02 mg Cyclosporin 0.050 g Corn starch 0.060 gLactose q.s. 0.300 g

The gel capsules used consist of gelatin, titanium oxide and apreserving agent.

In the treatment of psoriasis, 1 gel capsule per day is administered toan adult individual for 1 to 12 months.

2) Topical Route

(a) The nonionic water-in-oil cream below is prepared:

Compound of Example 10 0.100 g Mixture of emulsifying lanolin 39.900 galcohols, waxes and refined oils, sold by the company BDF under the name“Anhydrous eucerin” Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water q.s. 100.000 g

This cream is applied to skin afflicted with psoriasis 1 to 2 times aday for 1 to 12 months.

(b) A gel is prepared by preparing the formulation below:

Compound of Example 15 0.001 g Erythromycin base 4.000 gButylhydroxytoluene 0.050 g Hydroxypropylcellulose sold by the 2.000 gcompany Hercules under the name “Klucel HF” Ethanol (at 95°) q.s.100.000 g

This gel is applied to skin afflicted with dermatitis or with acne 1 to3 times a day for 6 to 12 weeks depending on the severity of the casetreated.

(c) An antiseborrhoeic lotion is prepared by mixing together thefollowing ingredients:

Compound of Example 12 0.030 g Propylene glycol 5.000 gButylhydroxytoluene 0.100 g Ethanol (at 95°) q.s. 100.000 g

This lotion is applied twice a day to a seborrhoeic scalp and asignificant improvement is observed within a period of 2 to 6 weeks.

(d) A cosmetic composition to combat the harmful effects of sunlight isprepared by mixing together the following ingredients:

Compound of Example 8 1.000 g Benzylidenecamphor 4.000 g Fatty acidtriglycerides 31.000 g Glyceryl monostearate 6.000 g Stearic acid 2.000g Cetyl alcohol 1.200 g Lanolin 4.000 g Preserving agents 0.300 gPropylene glycol 2.000 g Triethanolamine 0.500 g Fragrance 0.400 gDemineralized water q.s. 100.000 g

This composition is applied daily and helps to combat light-inducedageing.

(e) The nonionic oil-in-water cream below is prepared:

Compound of Example 7 0.500 g Retinoic acid 0.020 g Cetyl alcohol 4.000g Glyceryl monostearate 2.500 g PEG-50 stearate 2.500 g Karite butter9.200 g Propylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 gPropyl para-hydroxybenzoate 0.075 g Sterile demineralized water q.s.100.000 g

This cream is applied to skin afflicted with psoriasis, 1 to 2 times aday for 30 days for an attacking treatment, and indefinitely for amaintenance treatment.

(f) A topical gel is prepared by mixing together the followingingredients:

Compound of Example 11 0.050 g Ethanol 43.000 g α-Tocopherol 0.050 gCarboxyvinyl polymer sold under the 0.500 g name “Carbopol 941” by thecompany “Goodrich” Triethanolamine as an aqueous 3.800 g solution at 20%by weight Water 9.300 g Propylene glycol q.s. 100.000 g

This gel is applied in the treatment of acne 1 to 3 times a day for 6 to12 weeks depending on the severity of the case treated.

(g) A lotion for preventing hair loss and for promoting regrowth of thehair is prepared by mixing together the following ingredients:

Compound of Example 14 0.05 g Compound sold under the name 1.00 g“Minoxidil” Propylene glycol 20.00 g Ethanol 34.92 g Polyethylene glycol(molecular 40.00 g mass = 400) Butylhydroxyanisole 0.01 gButylhydroxytoluene 0.02 g Water q.s. 100.00 g

This lotion is applied 1 to 2 times a day for 3 months to a scalp whichhas suffered hair loss, and indefinitely for a maintenance treatment.

(h) An anti-acne cream is prepared by mixing together the followingingredients:

Compound of Example 5 0.050 g Retinoic acid 0.010 g Mixture of glycerylstearate and 15.000 g polyethylene glycol stearate (75 mol) sold underthe name “Gelot 64” by the company “Gattefosse” Polyoxyethylenatedkernel oil 8.000 g containing 6 mol of ethylene oxide, sold under thename “Labrafil M2130 CS” by the company “Gattefosse” Perhydrosqualene10.000 g Preserving agents q.s. Polyethylene glycol (molecular 8.000 gmass = 400) Disodium salt of ethylenediamine 0.050 g tetraacetic acidPurified water q.s. 100.000 g

This cream is applied to skin afflicted with dermatitis or acne 1 to 3times a day for 6 to 12 weeks.

(i) An oil-in-water cream is prepared by preparing the followingformulation:

Compound of Example 4 0.020 g Betamethasone 17-valerate 0.050 gS-carboxymethylcysteine 3.000 g Polyoxyethylene stearate (40 mol of4.000 g ethylene oxide) sold under the name “Myrj 52” by the company“Atlas” Sorbitan monolaurate 1.800 g polyoxyethylenated with 20 mol ofethylene oxide, sold under the name “Tween 20” by the company “Atlas”Mixture of glyceryl mono- and 4.200 g distearate sold under the name“Géléol” by the company “Gattefosse” Propylene glycol 10.000 gButylhydroxyanisole 0.010 g Butylhydroxytoluene 0.020 g Cetostearylalcohol 6.200 g Preserving agents q.s. Perhydrosqualene 18.000 g Mixtureof caprylic/capric 4.000 g triglyerides sold under the name “Miglyol812” by the company “Dynamit Nobel” Triethanolamine (99% by weight)2.500 g Water q.s. 100.000 g

This cream is applied twice a day to skin afflicted with inflammatorydermatitis, for 30 days.

(j) The oil-in-water cream below is prepared:

Lactic acid 5.000 g Compound of Example 1 0.020 g Polyoxyethylenestearate (40 mol of 4.000 g ethylene oxide) sold under the name “Myrj52” by the company “Atlas” Sorbitan monolaurate 1.800 gpolyoxyethylenated with 20 mol of ethylene oxide, sold under the name“Tween 20” by the company “Atlas” Mixture of glyceryl mono- and 4.200 gdistearate sold under the name “Geleol” by the company “Gattefosse”Propylene glycol 10.000 g Butylhydroxyanisole 0.010 gButylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g Preservingagents q.s. Perhydrosqualene 18.000 g Mixture of caprylic/capric 4.000 gtriglyerides sold under the name “Miglyol 812” by the company “DynamitNobel” Water q.s. 100.000 g

This cream is applied once a day, and helps to combat ageing, whetherlight-induced or chronological.

(k) The anhydrous ointment below is prepared:

Compound of Example 1 5.000 g Liquid petroleum jelly 50.00 gButylhydroxytoluene 0.050 g White petroleum jelly q.s. 100 g

This ointment is applied twice a day for 30 days to skin afflicted withsquamous dermatitis.

3) Intralesional Route

(a) The following composition is prepared:

Compound of Example 2 0.002 g Ethyl oleate q.s. 10 g

In the treatment of malignant melanoma, the composition is injected intoan adult individual at a frequency of 1 to 7 times a week for 1 to 12months.

(b) The following composition is prepared:

Compound of Example 1 0.050 g Olive oil q.s. 2 g

In the treatment of basocellular carcinoma, the composition is injectedinto an adult individual at a frequency of 1 to 7 times a week for 1 to12 months.

(c) The following composition is prepared:

Compound of Example 3 0.1 mg Sesame oil q.s. 2 g

In the treatment of spinocellular carcinoma, the composition is injectedinto an adult individual at a frequency of 1 to 7 times a week for 1 to12 months.

(d) The following composition is prepared:

Compound of Example 4 0.001 mg Methyl benzoate q.s. 10 g

In the treatment of carcinoma of the colon, the composition is injectedinto an adult individual at a frequency of 1 to 7 times a week for 1 to12 months.

4) Intravenous Route

(a) The injectable lipid emulsion below is prepared:

Compound of Example 4 0.001 mg Soyabean oil 10.000 g Egg phospholipid1.200 g Glycerol 2.500 g Water for injection q.s. 100.000 g

In the treatment of psoriasis, the composition is injected into an adultindividual at a frequency of 1 to 7 times a week for 1 to 12 months.

(b) The injectable lipid emulsion below is prepared:

Compound of Example 3 0.010 g Cotton Oil 10.000 g Soyabean lecithin0.750 g Sorbitol 5.000 g D,L-α-tocopherol 0.100 g Water for injectionq.s. 100.000 g

In the treatment of ichthyosis, the composition is injected into anadult individual at a frequency of 1 to 7 times a week for 1 to 12months.

(c) The injectable lipid emulsion below is prepared:

Compound of Example 2 0.001 g Soyabean oil 15.000 g Acetylatedmonoglycerides 10.000 g Pluronic F-108 1.000 g Glycerol 2.500 g Waterfor injection q.s. 100.000 g

In the treatment of leukaemia, the composition is injected into an adultindividual at a frequency of 1 to 7 times a week for 1 to 12 months.

(d) The mixed micellar composition below is prepared:

Compound of Example 2 0.001 g Lecithin 16.930 g Glycocholic acid 8.850 gWater for injection q.s. 100.000 g

In the treatment of malignant melanoma, the composition is injected intoan adult individual at a frequency of 1 to 7 times a week for 1 to 12months.

(e) The cyclodextrin composition below is prepared:

Compound of Example 1 0.1 mg β-Cyclodextrin 0.100 g Water for injectionq.s. 10.000 g

In the treatment of graft rejection, the composition is injected into anadult individual at a frequency of 1 to 7 times a week for 1 to 12months.

(f) The cyclodextrin composition below is prepared:

Compound of Example 4 0.010 g 2-Hydroxypropyl-β-cyclodextrin 0.100 gWater for injection q.s. 10.000 g

In the treatment of cancer of the kidney, the composition is injectedinto an adult individual at a frequency of 1 to 7 times a week for 1 to12 months.

EXAMPLE 17 Test Example to Evaluate the Biological Activity of theCompounds of the Invention

The VDR agonist activity was tested on the HeLa cell line, byco-transfection of an expression vector of the human VDR receptor and ofthe reporter plasmid p240Hase-CAT which contains the region −1399 to +76of the rat 24-hydroxylase promoter, cloned upstream of the coding frameof the chloramphenicol-acetyl-transferase (CAT) gene. 18 hours afterco-transfection, the test product is added to the medium. Aftertreatment for 18 hours, the CAT activity of the cell lysates is assayedby an ELISA test. The results are expressed as a percentage of theeffect normally observed with 10⁻⁷ M of calcitriol.

The agonist activity was characterized in this co-transfection system bydetermining the dose required to achieve 50% of the maximum activity ofthe product (AC50).

Test Compound AC 50 (nM) Example 1 192 Example 2 267 Example 4 294Example 6 61 Example 7 17 Example 8 29 Example 10 23 Example 12 655Example 13 78

What is claimed is:
 1. A compound of formula (I):

in which: R₁ represents a hydrogen atom, a CH₃ radical or a radical—(CH₂)_(s)—OR₄, R₂ represents a radical —(CH₂)_(t)—OR₅, s, t, R₄ and R₅having the meanings given below, X—Y represents a bonding group selectedfrom the bonding groups of formulae (a) to (i) below:

R₆ and W having the meanings given below, Z represents a ring selectedfrom the rings of formulae (j) to (n) below:

R₇ and R₈ having the meanings given below, it being understood that whenZ represents the rings of formula (k), (l) or (m), then X—Y cannotrepresent a bonding group of formula (c) or (d), it being understoodthat when Z represents a ring of formula (n), then X—Y represents abonding group of formula (c) or (d), R₃ represents an alkyl chaincontaining from 4 to 8 carbon atoms substituted with one or morehydroxyl groups, it being possible for the hydroxyl groups to beprotected in the form of acetoxy, methoxy or ethoxy, trimethylsilyloxy,tert-butyldimethylsilyloxy, tetrahydropyranyloxy and optionally also:substituted with one or more lower alkyl or cycloalkyl groups and/orsubstituted with one or more halogen atoms and/or substituted with oneor more CF₃ groups and/or in which one or more carbon atoms of the chainare replaced with oxygen, sulphur or nitrogen atoms, it being possiblefor the nitrogen atoms to be optionally substituted with lower alkylradicals and/or in which one or more single bonds of the chain arereplaced with one or more double and/or triple bonds, R₃ beingpositioned on the ring para or meta to the bonding group X—Y, s and t,which may be identical or different, being 1 or 2, R₄ and R₅, which maybe identical or different, represent a hydrogen atom, an acetyl radical,a benzoyl radical, a trimethylsilyl radical, a tert-butyldimethylsilylradical or a tetrahydropyranyl radical, R₆ represents a hydrogen atom ora lower alkyl radical, W represents an oxygen or sulphur atom or an —NH—radical which can optionally be substituted with a lower alkyl radical,R₇ represents a hydrogen atom or a lower alkyl radical, R₈ represents ahydrogen atom, a lower alkyl radical or a halogen atom, and the opticaland geometrical isomers of the said compounds of formula (I), and saltsthereof.
 2. A compound according to claim 1, in the form of a salt of aninorganic or organic acid.
 3. A compound according to claim 1, whereinthe lower alkyl radicals are selected from the group consisting ofmethyl, ethyl, isopropyl, tert-butyl and hexyl radicals.
 4. A compoundaccording to claim 1, wherein the cycloalkyl radical corresponds to acyclopropyl, cyclopentyl or cyclohexyl radical.
 5. A compound accordingto claim 1, wherein the halogen atom corresponds to a fluorine, chlorineor bromine atom.
 6. A compound according to claim 1, selected from thegroup consisting of:(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol,(E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethyloct-6-en-3-ol,(E)-7-[2-(3,4-bis-hydroxymethyl-phenoxymethyl)-4-thienyl]-3-ethyloct-6-en-3-ol,(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-pyridyl]-3-ethyloct-6-en-3-ol,(E)-7-[6-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-pyridyl)-3-ethylnon-6-en-3-ol,(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol,(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol,(3E,5E)-6-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1,2,2-pentafluoro-3-pentafluoroethylnona-4,6-dien-3-ol,(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethyl-4,4-dimethylnon-6-en-3-ol,(E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol,(4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol,(3E,5E)-6-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1,2,2-pentafluoro-3-pentafluoroethylnona-4,6-dien-3-ol,(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-benzylamino)-2-thienyl]-3-ethylnona-4,6-dien-3-ol,(4E,6E)-7-{5-[(3,4-bis-hydroxymethyl-benzyl)methylamino]-2-thienyl}-3-ethylnona-4,6-dien-3-ol,(4E,6E)-7-{5-[(3,4-bis-hydroxymethyl-benzyl)propylamino]-2-thienyl}-3-ethylnona-4,6-dien-3-ol,(E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnon-6-en-3-ol,(4E,6E)-7-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol,(3E,5E)-6-[4-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(E)-7-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol,(4E,6E)-7-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol,(3E,5E)-6-{4-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnon-6-en-3-ol,(4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-ol,(3E,5E)-6-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-3-ethylnon-6-en-3-ol(4E,6E)-7-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-3-ethylnona-4,6-dien-3-ol,and(3E,5E)-6-{5-[2-(3,4-bis-hydroxymethyl-phenyl)ethyl]-3-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol.7. A compound according to claim 1, which has at least one of thefollowing characteristics: R₁ represents a —CH₃ or —(CH₂)_(s)OH radical,R₂ represents a radical —(CH₂)_(t)OH, X—Y represents a bonding group offormula (b), (c), (h) or (g), and R₃ is selected from the groupconsisting of an alkyl or alkenyl chain of 4 to 8 carbon atomssubstituted with at least one hydroxyl radical and at least one loweralkyl radical, or an alkyl or alkenyl chain of 4 to 8 carbon atomssubstituted with at least one hydroxyl radical, at least one lower alkylradical and at least one CF₃ radical.
 8. A method for the treatment: ofdermatological complaints associated with a keratinization disorderwhich has a bearing on differentiation and on proliferation, of othertypes of keratinization disorders, of other dermatological complaintswith an inflammatory and/or immunoallergic component, with or withoutcell proliferation disorders, of dermal or epidermal proliferations,whether benign or malignant and whether they are of viral origin orotherwise, of other dermatological disorders comprising lupuserythematosus, immune bullosis and collagen diseases, of dermatologicalor general complaints with an immunological component, of disorders ofsebaceous function, of skin disorders due to exposure to UV radiation,aging of the skin, whether it is light-induced or chronological aging,or pigmentations and actinic keratoses, or any pathologies associatedwith chronological or actinic aging, of cicatrization disorders orstretchmarks, of inflammatory complaints comprising arthritis, anycomplaint of viral origin on the skin or generally, of ophthalmologicaldisorders, of cancerous or pre-cancerous states of cancers presenting orpossibly being induced by vitamin D receptors, of alopecia of variousorigins, of immune system or autoimmune diseases, or of immunerejection, of endocrine complaints, of complaints associated withabnormal management of intracellular calcium, and of pathologies inwhich calcium metabolism is involved; of vitamin D deficiencies andother mineral homeostasis complaints in plasma and bone, of complaintsof the cardiovascular system, or of non-insulin-dependent diabetes,comprising administering an effective amount of at least one compoundaccording to claim 1 to a patient in need of such treatment.
 9. Themethod of claim 8, wherein said vitamin D deficiency or other mineralhomeostasis complaint is rickets, osteomalacia, or osteoporosis.
 10. Apharmaceutical composition comprising, in a pharmaceutically acceptablesupport, at least one of the compounds as defined in claim
 1. 11. Apharmaceutical composition according to claim 10, wherein theconcentration of compound(s) is between 0.0001% and 5% by weightrelative to the total weight of the composition.
 12. A cosmeticcomposition, comprising, in a cosmetically acceptable support, at leastone of the compounds as defined in claim
 1. 13. A cosmetic compositionaccording to claim 12, wherein the concentration of compound(s) isbetween 0.001% and 3% by weight relative to the total weight of thecomposition.
 14. A method for body or hair hygiene comprisingadministering an effective amount of at least one compound according toclaim 1 to a patient in need thereof.